Compositions and methods for treating, ameliorating and preventing h. pylori infections

ABSTRACT

Provided are methods for treating, ameliorating, reversing and/or preventing a Helicobacter pylori (H. pylori) infection in an individual in need thereof, comprising: administering to the individual in need thereof a therapeutic combination comprising: (a) a composition comprising or consisting of: vonoprazan or a vonoprazan fumarate, or a 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine monofumarate, or a 1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine fumarate), optionally TAKECAB™; and (b) an antimicrobial or antibiotic drug or composition.

RELATED APPLICATIONS

This application is a continuation application claiming benefit ofpriority to Patent Cooperation Treaty (PCT) International ApplicationSerial No: PCT/AU2018/000195, filed Oct. 15, 2018, which claims benefitof priority to U.S. Provisional Patent Application Ser. No. (“USSN”)62/572,512, filed Oct. 15, 2017. The aforementioned applications areexpressly incorporated herein by reference in their entirety and for allpurposes.

TECHNICAL FIELD

This invention generally relates to infectious diseases and medicine. Inalternative embodiments, provided are therapeutic combinations,including products of manufacture and kits, and methods, for treating,ameliorating, reversing and/or preventing (acting as a prophylaxis) aHelicobacter pylori (H. pylori) infection in an individual in needthereof.

BACKGROUND

The history of Helicobacter pylori (H. pylori) eradication dates back to1984 when the first triple therapy was developed in Australia by Borodyat the Centre for Digestive Diseases. It consisted of Bismuth,Tetracycline, and Flagyl. Its long term effects were reported in 1989and it was dispensed to patients as a separately-prescribed combinationwritten on prescriptions by most physicians until the commercial productcalled Helidac was placed on the market in several countries. Since thattime numerous Triple Therapies have been described with the one mostutilised being a combination consisting of a Proton Pump Inhibitor(PPI), amoxicillin and clarithromycin. However, there has been aprogressive fall in the efficacy of this combination due to H. pylorideveloping resistance to clarithromycin and hence, alternate therapiesare being sought.

In Japan a new acid suppressant called vonoprazan or vonoprazan fumarate[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate], also sold as TAKECAB™ (CAS#:1260141-27-2,1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminefumarate), which is a potassium-competitive acid blocker has beenapproved. It causes prolonged and profound inhibition of gastric acidsecretion and has gained clinical acceptance in treating erosiveoesophagitis and peptic ulcers. An unusual, but useful advantage ofvonoprazan over a Proton Pump Inhibitor (PPI) in the amoxicillin andclarithromycin combination is that the efficacy increases quitemarkedly. This is without any added adverse events nor any more thanobserved with the standard triple therapies with conventional ProtonPump Inhibitors (PPIs).

The chemical advantage of vonoprazan is that it does not require acidfor activation. It is rapidly absorbed in the intestine and leads tofast inhibition of acid secretion. It is more stable at neutral pHcompared with conventional PPI's and has plasma half-life of 7 hoursafter a single 20 mg ingestion. This is longer than the conventionalPPI's which have a half-life less than 2 hours permitting the gastric pHto fall back into acidic range. It is not metabolised through thehepatic CYP2C19 haplotypes, but rather by the CYP3A4 system. For thisreason, vonoprazan exerts rapid, strong, prolonged and stable inhibitionof H⁺/K⁺—ATPAs (ATP synthase subunit alpha). Vonoprazan manages toincrease intragastric pH to at least over pH 4.0 within 4 hours of itsfirst administration in humans creating conditions within which theantibiotics amoxicillin and clarithromycin are stable in conjunction.

As a result of vonoprazan's pH elevating activity when compared it hasbeen observed that the H. pylori (HP) eradication rate with vonoprazan,amoxicillin and clarithromycin has frequently resulted in 93%eradication with versus (vs.) 76% eradication with lansoprazole (PPI) asfirst line therapy. Other studies have showed similar wide efficacydifferences with vonoprazan vs PPI combinations, many of them over 92%.Most have ranged between 88% and 94% as first line therapy. Vonoprazanhas been used as ‘Second Line Therapy’ using metronidazole, amoxicillin,and vonoprazan twice daily for 7 days reaching an eradication rate ofclose to 100%. The vonoprazan, amoxicillin and clarithromycin still hasa fairly high eradication rate in the low 80's. It is the enhancedactivity of the amoxicillin (although not as effective as whencontaining an added clarithromycin) which makes the eradication sopowerful to the extent that dual therapy with amoxicillin and vonoprazanhas been proposed as a potential ‘First Line’ therapy.

While these therapies have achieved some degree of success, asignificant number of treatments still remain failures (see e.g.,Akazawa Y et al. 2016, Therap Adv Gastroenterol, 9:845) which can resultin adverse effects in the non-responding patients and antibioticresistance in non-responders. To be clinically effective or useful, H.pylori (HP) eradication efficacy of a therapeutic regimen should reachclose to or over 90%—otherwise it is not sufficiently clinicallyeffective. The existing amoxicillin and clarithromycin PPI protocolswere initially able to achieve greater than 85% eradication and becamethe “standard of care protocols” in many parts of the world. However,the rising resistance to clarithromycin has brought an end to theclinical usefulness of this combination in numerous regions of theworld. Some eradication rates have fallen from 90% down to less than50%.

SUMMARY

In alternative embodiments, provided are methods for treating,ameliorating, reversing and/or preventing (acting as a prophylaxis) aHelicobacter pylori (H. pylori) infection in an individual in needthereof, comprising:

-   administering to the individual in need thereof a therapeutic    combination comprising:-   (a) a composition comprising or consisting of: vonoprazan or a    vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™; and-   (b) an antimicrobial or antibiotic drug or composition comprising or    consisting of:    (i)-   (1) an amoxicillin, administered to the individual in need thereof    at a dose of between about 1 gram (g) to about 2 g twice daily    (bid), and optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, also known as co-amoxiclav, or is    optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™;    and-   (2) a clarithromycin, optionally BIAXIN™, administered to the    individual in need thereof at a dose of between about 100 mg to    about 2 g twice daily, wherein the vonoprazan or a vonoprazan    fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is administered to the individual in    need thereof at a dose of between 20 mg to about 50 mg twice daily    (bid), or for about 25 mg or more twice daily (bid);    (ii)-   (1) an amoxicillin, administered to the individual in need thereof    at a dose of between about 500 gm to about 1 g three times daily    (tid), and optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, also known as co-amoxiclav, or is    optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™;    and-   (2) a metronidazole, optionally FLAGYL™, METRO™, administered to the    individual in need thereof at a dose of between about 200 mg to    about 500 mg three times daily (tid),    wherein the vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is administered to the individual in    need thereof at a dose of between 20 mg to about 50 mg three times    daily (tid), or for about 25 mg or more three times daily (tid);    (iii)-   (1) an amoxicillin, administered to the individual in need thereof    at a dose of between about 250 gm to about 1 g twice daily (bid) or    three times daily (tid), and optionally the amoxicillin is    formulated as amoxicillin/ clavulanic acid, also known as    co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™,    TYCIL™, AMOXIL™, TRIMOX™; and-   (2) a rifabutin, optionally MYCOBUTIN™, administered to the    individual in need thereof at a dose of between about 50 mg to about    250 mg twice daily (bid) or three times daily (tid),    wherein the vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is administered to the individual in    need thereof at a dose of between 5 mg to about 200 mg or more twice    daily (bid) or three times daily (tid);    (iv)-   (1) an amoxicillin, administered to the individual in need thereof    at a dose of between about 250 gm to about 1 g twice daily (bid) or    three times daily (tid), and optionally the amoxicillin is    formulated as amoxicillin/ clavulanic acid, also known as    co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™,    TYCIL™, AMOXIL™, TRIMOX™; and-   (2) a levofloxacin, administered to the individual in need thereof    at a dose of between about 100 mg to about 500 mg twice daily (bid)    or three times daily (tid), wherein the vonoprazan or a vonoprazan    fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is administered to the individual in    need thereof at a dose of between 5 mg to about 200 mg or more twice    daily (bid) or three times daily (tid);    (v)-   (1) an amoxicillin, administered to the individual in need thereof    at a dose of between about 250 gm to about 1 g twice daily (bid) or    three times daily (tid), and optionally the amoxicillin is    formulated as amoxicillin/ clavulanic acid, also known as    co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™,    TYCIL™, AMOXIL™, TRIMOX™; and-   (2) a ciprofloxacin, optionally CILOXAN™, CIPRO™, NEOFLOXIN™    administered to the individual in need thereof at a dose of between    about 100 mg to about 500 mg twice daily (bid) or three times daily    (tid),    wherein the vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is administered to the individual in    need thereof at a dose of between 5 mg to about 200 mg or more twice    daily (bid) or three times daily (tid);    (vi)-   (1) an amoxicillin, administered to the individual in need thereof    at a dose of between about 250 gm to about 1 g twice daily (bid) or    three times daily (tid), and optionally the amoxicillin is    formulated as amoxicillin/ clavulanic acid, also known as    co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™,    TYCIL™, AMOXIL™, TRIMOX™; and-   (2) a moxifloxacin, optionally AVELOX™, VIGAMOX™, MOXEZA™    administered to the individual in need thereof at a dose of between    about 25 mg to about 500 mg per day,    wherein the vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is administered to the individual in    need thereof at a dose of between 5 mg to about 200 mg or more twice    daily (bid) or three times daily (tid);    (vii)-   (1) an amoxicillin, a clarithromycin, a metronidazole, a    levofloxacin, a ciprofloxacin or a moxifloxacin, administered to the    individual in need thereof at a dose as set forth in any of    steps (i) to (vi), and optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, also known as co-amoxiclav, or is    optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™;    and-   (2) a TG44, or a 1-1000 mg/d] {[4-methylbenzyl    4′-[trans-4-(guanidine-methyl) cyclohexyl carbonyloxy]    biphenyl-4-carboxylate monohydrochloride}, or CAS registry number    178748-55-5, administered to the individual in need thereof at a    dose of between about 15 mg to about 50 mg per day, or at about 50    to 500 mg per day, wherein the vonoprazan or a vonoprazan fumarate,    or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is administered to the individual in    need thereof at a dose of between 5 mg to about 50 mg, or 20 mg or    more, twice daily (bid) or three times daily (tid);    (viii)-   (1) an amoxicillin,-   (2) a furazolidone, optionally FUROXONE™, DEPENDAL-M™, administered    to the individual in need thereof at a dose of between about 50 to    about 600 mg/d, and-   (3) a rifabutin, optionally MYCOBUTIN™, administered to the    individual in need thereof at a dose of between about 60 to about    450 mg/d, and optionally the rifabutin dose is ramped up starting at    about 40 to about 60 g bid or tid, and optionally rising over 3 days    to about 200 to about 450/d,    wherein the vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is administered to the individual in    need thereof at a dose as set forth in any of (i) to (vii);-   (ix) a therapeutic combination as set forth in Table 1; or-   (x) any combination of (i) to (ix).

In alternative embodiments there is provided a method for treating orpreventing Helicobacter pylori (H. pylori) infection in an individual inneed thereof, the method comprising administering to the individual inneed thereof a therapeutic combination comprising:

-   (a) vonoprazan, and-   (b) a prolonged release formulation of an antibiotic comprising:-   (1) amoxicillin wherein optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, and/or-   (2) an antibiotic selected from the group consisting of    clarithromycin, azithromycin, roxithromycin and erythromycin,    wherein the vonoprazan is administered in an amount of 10 mg to 1 g    per day, and the amoxicillin is administered in an amount of 10 mg    to 6 g per day.

In alternative embodiments there is provided a method for treating orpreventing Helicobacter pylori (H. pylori) infection in an individual inneed thereof, the method comprising administering to the individual inneed thereof a therapeutic combination comprising:

-   (a) a prolonged release microencapsulated and/or multimatrix    formulation of vonoprazan, and-   (b) a prolonged release microencapsulated and/or multimatrix    formulation of amoxicillin wherein optionally the amoxicillin is    formulated as amoxicillin/clavulanic acid, or-   (c) a prolonged release microencapsulated and/or multimatrix    formulation of vonoprazan and amoxicillin wherein optionally the    amoxicillin is formulated as amoxicillin/clavulanic acid,    wherein the vonoprazan is administered in an amount of 10 mg to 1 g    per day, and the amoxicillin is administered in an amount of 1 g to    6 g per day.

In alternative embodiments there is provided a method for treating orpreventing Helicobacter pylori (H. pylori) infection in an individual inneed thereof, the method comprising administering to the individual inneed thereof a therapeutic combination comprising:

-   (a) vonoprazan,-   (b) a proton pump inhibitor, and-   (c) at least one antibiotic selected from the group consisting of    amoxicillin, wherein optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, ampicillin, pivampicillin, hetacillin,    bacampicillin, metampicillin, talampicillin, epicillin, a macrolide    antibiotic, furazolidone, ciprofloxacin, levofloxacin, tetracycline,    a nitroimidazole antibiotic, bismuth, an ansamycin antibiotic, and    nitazoxanide, wherein optionally the proton pump inhibitor is    selected from the group consisting of omeprazole; pantoprazole;    esomeprazole, lansoprazole, and rabeprazole, wherein optionally the    macrolide antibiotic is selected from the group consisting of    azithromycin, clarithromycin, erythromycin, fidaxomicin, and    telithromycin,-   wherein optionally the nitroimidazole antibiotic is selected from    the group consisting of metronidazole, tinidazole, and secnidazole,-   wherein optionally the ansamycin antibiotic is selected from the    group consisting of rifabutin, rifampicin, rifapentin, and    rifamixin.

In alternative embodiments there is provided a method for treating orpreventing Helicobacter pylori (H. pylori) infection in an individual inneed thereof, the method comprising administering to the individual inneed thereof a therapeutic combination comprising

-   (i) amoxicillin, vonoprazan, furazolidone, and rifabutin;-   (ii) amoxicillin, vonoprazan, bismuth, furazolidone, rifabutin;-   (iii) amoxicillin, vonoprazan, bismuth, levofloxacin, rifabutin;-   (iv) amoxicillin, vonoprazan, levofloxacin, rifabutin;-   (v) amoxicillin, vonoprazan, bismuth, levofloxacin, furazolidone,    rifabutin;-   (v) amoxicillin, vonoprazan, bismuth, tetracycline, rifabutin;-   (vi) metronidazole, vonoprazan, bismuth, tetracycline, rifabutin;-   (v) vonoprazan, bismuth, levofloxacin, rifabutin; or-   (vi) amoxicillin, vonoprazan, furazolidone, rifabutin, bismuth, and    nitazoxanide,    wherein optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid.

In alternative embodiments of methods as provided herein: thetherapeutic combination is administered to the individual in needthereof for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 or moredays; or the therapeutic combination is, is contained in or comprises aformulation, a pharmaceutical preparation or a pharmaceuticalcomposition.

In alternative embodiments of methods as provided herein: the vonoprazanor vonoprazan fumarate, or the5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or the1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof:

-   (a) at a unit dosage of between about 5 mg to about 200 mg per day,    or-   (b) in a unit dosage form of between about 10 mg and 200 mgm, or    between about between about 40 mg and 100 mgm, or is about 10, 20,    30, 40, 50, 60, 70, 75, 80, 90 or 100 mg per unit dose,    which optionally can be administered once a day, bid or tid, or a    four times a day, five times a day or six times a day or more,    regimen.

In alternative embodiments of methods as provided herein: thetherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, is formulated as a chewable deliveryvehicle, a gum, a gummy, a candy, a lozenge, an ice cream or an ice, ora yogurt.

In alternative embodiments of methods as provided herein: thetherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, further comprises a flavoring or asweetening agent, an aspartamine, a stevia, monk fruit, a sucralose, asaccharin, a cyclamate, a xylitol, a vanilla, an artificial vanilla orchocolate or strawberry flavor, an artificial chocolate essence, or amixture or combination thereof.

In alternative embodiments of methods as provided herein: thetherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, further comprises a preservative, a benzoicacid or a potassium sorbate.

In alternative embodiments of methods as provided herein: thetherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, further comprises, or has added to: at leastone probiotic or prebiotic, wherein optionally the prebiotic comprisesan inulin, lactulose, extracts of artichoke, chicory root, oats, barley,various legumes, garlic, kale, beans, flax or an herb, whereinoptionally the probiotic comprises a cultured or stool-extractedmicroorganism or bacteria, or a bacterial component, and optionally thebacteria or bacterial component comprises or is derived from aSaccharomyces boulardii, Bacteroidetes, a Firmicutes, a Lactobacilli, aBifidobacteria, an E coli, a Strep fecalis and equivalents.

In alternative embodiments of methods as provided herein: thetherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, further comprises, or has added to: at leastone congealing agent, wherein optionally the congealing agent comprisesan arrowroot or a plant starch, a powdered flour, a powdered potato orpotato starch, an absorbant polymer, an Absorbable Modified Polymer,and/or a corn flour or a corn starch.

In alternative embodiments of methods as provided herein: thetherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, further comprises an additive selected fromone or more of a saline, a media, a defoaming agent, a surfactant agent,a lubricant, an acid neutralizer, a marker, a cell marker, a drug, anantibiotic, a contrast agent, a dispersal agent, a buffer or a bufferingagent, a sweetening agent, a debittering agent, a flavoring agent, a pHstabilizer, an acidifying agent, a preservative, a desweetening agentand/or coloring agent, vitamin, mineral and/or dietary supplement, or aprebiotic nutrient.

In alternative embodiments of methods as provided herein: thetherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, further comprises, or has added to: at leastone Biofilm Disrupting Compound, wherein optionally the biofilmdisrupting compound comprises an enzyme, a deoxyribonuclease (DNase),N-acetylcysteine, an auranofin, an alginate lyase, glycoside hydrolasedispersin B; a Quorum-sensing inhibitor, a ribonucleic acid IIIinhibiting peptide, Salvadora persica extracts, Competence-stimulatingpeptide, Patulin and penicillic acid; peptides—cathelicidin-derivedpeptides, small lytic peptide, PTP-7, Nitric oxide, neo-emulsions;ozone, lytic bacteriophages, lactoferrin, xylitol hydrogel, syntheticiron chelators, cranberry components, curcumin, silver nanoparticles,Acetyl-11-keto-β-boswellic acid (AKBA), barley coffee components,probiotics, sinefungin, S-adenosylmethionine, S-adenosyl-homocysteine,Delisea furanones, N-sulfonyl homoserine lactones or any combinationthereof.

In alternative embodiments, the therapeutic combination, or theformulation, the pharmaceutical or the pharmaceutical preparation,further comprises, or has added to a statin selected from the groupconsisting of atorvastatin, fluvastatin, lovastatin, pitavastatin,pravastatin, rosuvastatin, and simvastatin.

In alternative embodiments the therapeutic combination, or theformulation, the pharmaceutical or the pharmaceutical preparation,further comprises, or has added to a pronase. Pronase refers to amixture of several nonspecific endo- and exoproteases that digestproteins down to single amino acids.

In alternative embodiments of methods as provided herein: thetherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, is formulated as a delayed or gradualenteric release composition or formulation, and optionally theformulation comprises a gastro-resistant coating designed to dissolve ata pH of 7 in the terminal ileum, e.g., an active ingredient is coatedwith an acrylic based resin or equivalent, e.g., a poly(meth)acrylate,e.g. a methacrylic acid copolymer B, NF, which dissolves at pH 7 orgreater, e.g., comprises a multimatrix (MMX) formulation. Also providedis the therapeutic combination or composition of the inventionformulated as a microencapsulated product, wherein a proportion of thecombination or composition is released in stomach with an appropriate‘exploder’ excipient and a proportion of the combination or compositionis formulated in a MMX formulation, so as to deliver the combination orcomposition to the stomach immediately as well as to the small bowel forre-secretion into to stomach where the H. pylori resides.

In alternative embodiments of methods as provided herein: thetherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, is contained in a delivery vehicle, productof manufacture, container, syringe, device or bag.

In alternative embodiments of methods as provided herein: thetherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, is initially manufactured or formulated as aliquid, a suspension, a gel, a geltab, a semisolid, a tablet, a sachet,a lozenge or a capsule, or as an enteral formulation, or re-formulatedfor final delivery as a liquid, a suspension, a gel, a geltab, asemisolid, a tablet, a sachet, a lozenge or a capsule, or as an enteralformulation.

In alternative embodiments, provided are therapeutic combinationscomprising:

-   (a) a composition comprising or consisting of: vonoprazan or a    vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™; and-   (b) an antimicrobial or antibiotic drug or composition comprising or    consisting of:    (i)-   (1) an amoxicillin, formulated for administration to the individual    in need thereof at a dose of between about 1 gram (g) to about 2 g    twice daily (bid), and optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, also known as co-amoxiclav, or is    optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™;    and-   (2) a clarithromycin, optionally BIAXIN™, formulated for    administration to the individual in need thereof at a dose of    between about 100 mg to about 2 g twice daily, wherein the    vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is formulated for administration to    the individual in need thereof at a dose of between 20 mg to about    50 mg twice daily (bid), or for about 25 mg or more twice daily    (bid);    (ii)-   (1) an amoxicillin, formulated for administration to the individual    in need thereof at a dose of between about 500 gm to about 1 g three    times daily (tid), and optionally the amoxicillin is formulated as    amoxicillin/ clavulanic acid, also known as co-amoxiclav, or is    optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™;    and-   (2) a metronidazole, optionally FLAGYL™, METRO™, formulated for    administration to the individual in need thereof at a dose of    between about 200 mg to about 500 mg three times daily (tid),    wherein the vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is formulated for administration to    the individual in need thereof at a dose of between 20 mg to about    50 mg three times daily (tid), or for about 25 mg or more three    times daily (tid);    (iii)-   (1) an amoxicillin, formulated for administration to the individual    in need thereof at a dose of between about 250 gm to about 1 g twice    daily (bid) or three times daily (tid), and optionally the    amoxicillin is formulated as amoxicillin/ clavulanic acid, also    known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,    AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and-   (2) a rifabutin, optionally MYCOBUTIN™, formulated for    administration to the individual in need thereof at a dose of    between about 50 mg to about 250 mg twice daily (bid) or three times    daily (tid),    wherein the vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is formulated for administration to    the individual in need thereof at a dose of between 5 mg to about    200 mg or more twice daily (bid) or three times daily (tid);    (iv)-   (1) an amoxicillin, formulated for administration to the individual    in need thereof at a dose of between about 250 gm to about 1 g twice    daily (bid) or three times daily (tid), and optionally the    amoxicillin is formulated as amoxicillin/ clavulanic acid, also    known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,    AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and-   (2) a levofloxacin, formulated for administration to the individual    in need thereof at a dose of between about 100 mg to about 500 mg    twice daily (bid) or three times daily (tid),    wherein the vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is formulated for administration to    the individual in need thereof at a dose of between 5 mg to about    200 mg or more twice daily (bid) or three times daily (tid);    (v)-   (1) an amoxicillin, formulated for administration to the individual    in need thereof at a dose of between about 250 gm to about 1 g twice    daily (bid) or three times daily (tid), and optionally the    amoxicillin is formulated as amoxicillin/ clavulanic acid, also    known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,    AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and-   (2) a ciprofloxacin, optionally CILOXAN™, CIPRO™, NEOFLOXIN™,    formulated for administration to the individual in need thereof at a    dose of between about 100 mg to about 500 mg twice daily (bid) or    three times daily (tid),    wherein the vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is formulated for administration to    the individual in need thereof at a dose of between 5 mg to about    200 mg or more twice daily (bid) or three times daily (tid);    (vi)-   (1) an amoxicillin, formulated for administration to the individual    in need thereof at a dose of between about 250 gm to about 1 g twice    daily (bid) or three times daily (tid), and optionally the    amoxicillin is formulated as amoxicillin/ clavulanic acid, also    known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,    AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and-   (2) a moxifloxacin, optionally AVELOX™, VIGAMOX™, MOXEZA™,    formulated for administration to the individual in need thereof at a    dose of between about 25 mg to about 500 mg per day,    wherein the vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is formulated for administration to    the individual in need thereof at a dose of between 5 mg to about    200 mg or more twice daily (bid) or three times daily (tid);    (vii)-   (1) an amoxicillin, a clarithromycin, a metronidazole, a    levofloxacin, a ciprofloxacin or a moxifloxacin, formulated for    administration to the individual in need thereof at a dose as set    forth in any of steps (i) to (vi), and optionally the amoxicillin is    formulated as amoxicillin/ clavulanic acid, also known as    co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™,    TYCIL™, AMOXIL™, TRIMOX™; and-   (2) a TG44, or a 1-1000 mg/d] {[4-methylbenzyl    4′-[trans-4-(guanidine-methyl) cyclohexyl carbonyloxy] biphenyl    -4-carboxylate monohydrochloride}, or CAS registry number    178748-55-5, formulated for administration to the individual in need    thereof at a dose of between about 15 mg to about 50 mg per day, or    at about 50 to 500 mg per day,    wherein the vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is formulated for administration to    the individual in need thereof at a dose of between 5 mg to about 50    mg, or 20 mg or more, twice daily (bid) or three times daily (tid);    (viii)-   (1) an amoxicillin,-   (2) a furazolidone, optionally FUROXONE™, DEPENDAL-M™, formulated    for administration to the individual in need thereof at a dose of    between about 50 to about 600 mg/d, and-   (3) a rifabutin, optionally MYCOBUTIN™, formulated for    administration to the individual in need thereof at a dose of    between about 60 to about 450 mg/d, and optionally the rifabutin    dose is ramped up starting at about 40 to about 60 g bid or tid, and    optionally rising over 3 days to about 200 to about 450/d,    wherein the vonoprazan or a vonoprazan fumarate, or a    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or a    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is formulated for administration to    the individual in need thereof at a dose as set forth in any of (i)    to (vii);-   (ix) a therapeutic combination as set forth in Table 1; or-   (x) any combination of (i) to (ix).

In alternative embodiments, provided are kits or products of manufacturecomprising a therapeutic combination as provided herein.

In alternative embodiments, provided are uses of a therapeuticcombination as provided herein, or a kit or product of manufacture asprovided herein, in the manufacture of a medicament.

In alternative embodiments, provided are therapeutic combinations foruse in treating, ameliorating, reversing and/or preventing (acting as aprophylaxis) a Helicobacter pylori (H. pylori) infection in anindividual in need thereof, wherein the therapeutic combinationcomprises a therapeutic combination as provided herein.

The details of one or more exemplary embodiments of the invention areset forth in the accompanying drawings and the description below. Otherfeatures, objects, and advantages of the invention will be apparent fromthe description and drawings, and from the claims.

All publications, patents, patent applications cited herein are herebyexpressly incorporated by reference for all purposes.

In a first aspect, forms of the invention described herein include thefollowing:

-   1. A method for treating, ameliorating, reversing and/or preventing    (acting as a prophylaxis) a Helicobacter pylori (H. pylori)    infection in an individual in need thereof, comprising:

administering to the individual in need thereof a therapeuticcombination comprising:

(a) a composition comprising or consisting of: vonoprazan or avonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™; and

(b) an antimicrobial or antibiotic drug or composition comprising orconsisting of:

(i)

-   -   (1) an amoxicillin, administered to the individual in need        thereof at a dose of between about 1 gram (g) to about 2 g twice        daily (bid), optionally the amoxicillin is formulated as        amoxicillin/ clavulanic acid, also known as co-amoxiclav, or is        optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™,        TRIMOX™; and    -   (2) a clarithromycin, optionally BIAXIN™, administered to the        individual in need thereof at a dose of between about 100 mg to        about 2 g twice daily,

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 20 mg to about 50 mg twice daily(bid), or for about 25 mg or more twice daily (bid);

(ii)

-   -   (1) an amoxicillin, administered to the individual in need        thereof at a dose of between about 500 gm to about 1 g three        times daily (tid), and optionally the amoxicillin is formulated        as amoxicillin/ clavulanic acid, also known as co-amoxiclav, or        is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™,        TRIMOX™; and    -   (2) a metronidazole, optionally FLAGYL™, METRO™, administered to        the individual in need thereof at a dose of between about 200 mg        to about 500 mg three times daily (tid),

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 20 mg to about 50 mg three times daily(tid), or for about 25 mg or more three times daily (tid);

(iii)

-   -   (1) an amoxicillin, administered to the individual in need        thereof at a dose of between about 250 gm to about 1 g twice        daily (bid) or three times daily (tid), and optionally the        amoxicillin is formulated as amoxicillin/clavulanic acid, also        known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,        AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a rifabutin, optionally MYCOBUTIN™, administered to the        individual in need thereof at a dose of between about 50 mg to        about 250 mg twice daily (bid) or three times daily (tid),

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 200 mg or more twicedaily (bid) or three times daily (tid);

(iv)

-   -   (1) an amoxicillin, administered to the individual in need        thereof at a dose of between about 250 gm to about 1 g twice        daily (bid) or three times daily (tid), and optionally the        amoxicillin is formulated as amoxicillin/clavulanic acid, also        known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,        AMOCLA™, TYCIL™, AMOXIL™,

TRIMOX™; and

-   -   (2) a levofloxacin, administered to the individual in need        thereof at a dose of between about 100 mg to about 500 mg twice        daily (bid) or three times daily (tid),

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 200 mg or more twicedaily (bid) or three times daily (tid);

(v)

-   -   (1) an amoxicillin, administered to the individual in need        thereof at a dose of between about 250 gm to about 1 g twice        daily (bid) or three times daily (tid), and optionally the        amoxicillin is formulated as amoxicillin/clavulanic acid, also        known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,        AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a ciprofloxacin, optionally CILOXAN™, CIPRO™, NEOFLOXIN™        administered to the individual in need thereof at a dose of        between about 100 mg to about 500 mg twice daily (bid) or three        times daily (tid),

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 200 mg or more twicedaily (bid) or three times daily (tid);

(vi)

-   -   (1) an amoxicillin, administered to the individual in need        thereof at a dose of between about 250 gm to about 1 g twice        daily (bid) or three times daily (tid), and optionally the        amoxicillin is formulated as amoxicillin/clavulanic acid, also        known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,        AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a moxifloxacin, optionally AVELOX™, VIGAMOX™, MOXEZA™        administered to the individual in need thereof at a dose of        between about 25 mg to about 500 mg per day,

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 200 mg or more twicedaily (bid) or three times daily (tid);

(vii)

-   -   (1) an amoxicillin, a clarithromycin, a metronidazole, a        levofloxacin, a ciprofloxacin or a moxifloxacin, administered to        the individual in need thereof at a dose as set forth in any of        steps (i) to (vi), optionally the amoxicillin is formulated as        amoxicillin/ clavulanic acid, also known as co-amoxiclav, or is        optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™,        TRIMOX™; and    -   (2) a TG44, or a 1-1000 mg/d] {[4-methylbenzyl        4′-[trans-4-(guanidine-methyl) cyclohexyl        carbonyloxy]biphenyl-4-carboxylate monohydrochloride}, or CAS        registry number 178748-55-5, administered to the individual in        need thereof at a dose of between about 15 mg to about 50 mg per        day, or at about 50 to 500 mg per day,

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 50 mg, or 20 mg or more,twice daily (bid) or three times daily (tid);

(viii)

-   -   (1) an amoxicillin,    -   (2) a furazolidone, optionally FUROXONE™, DEPENDAL-M™,        administered to the individual in need thereof at a dose of        between about 50 to about 600 mg/d, and    -   (3) a rifabutin, optionally MYCOBUTIN™, administered to the        individual in need thereof at a dose of between about 60 to        about 450 mg/d, and optionally the rifabutin dose is ramped up        starting at about 40 to about 60 g bid or tid, and optionally        rising over 3 days to about 200 to about 450/d,

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose as set forth in any of (i) to (vii);

(ix) a therapeutic combination as set forth in Table 1; or

(x) any combination of (i) to (ix).

-   2. A method for treating or preventing Helicobacter pylori (H.    pylori) infection in an individual in need thereof, the method    comprising administering to the individual in need thereof a    therapeutic combination comprising:-   (a) vonoprazan, and-   (b) a prolonged release formulation of an antibiotic comprising:-   (1) amoxicillin wherein optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, and/or-   (2) an antibiotic selected from the group consisting of    clarithromycin, azithromycin, roxithromycin and erythromycin,    wherein the vonoprazan is administered in an amount of 10 mg to 1 g    per day, and the amoxicillin is administered in an amount of 10 mg    to 6 g per day.-   3. A method for treating or preventing Helicobacter pylori (H.    pylori) infection in an individual in need thereof, the method    comprising administering to the individual in need thereof a    therapeutic combination comprising:-   (a) a prolonged release microencapsulated and/or multimatrix    formulation of vonoprazan, and-   (b) a prolonged release microencapsulated and/or multimatrix    formulation of amoxicillin wherein optionally the amoxicillin is    formulated as amoxicillin/clavulanic acid, or-   (c) a prolonged release microencapsulated and/or multimatrix    formulation of vonoprazan and amoxicillin wherein optionally the    amoxicillin is formulated as amoxicillin/clavulanic acid,    wherein the vonoprazan is administered in an amount of 10 mg to 1 g    per day, and the amoxicillin is administered in an amount of 1 g to    6 g per day.-   4. A method for treating or preventing Helicobacter pylori (H.    pylori) infection in an individual in need thereof, the method    comprising administering to the individual in need thereof a    therapeutic combination comprising:-   (a) vonoprazan,-   (b) a proton pump inhibitor, and-   (c) at least one antibiotic selected from the group consisting of    amoxicillin, wherein optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, ampicillin, pivampicillin, hetacillin,    bacampicillin, metampicillin, talampicillin, epicillin, a macrolide    antibiotic, furazolidone, ciprofloxacin, levofloxacin, tetracycline,    a nitroimidazole antibiotic, bismuth, an ansamycin antibiotic, and    nitazoxanide,-   wherein optionally the proton pump inhibitor is selected from the    group consisting of omeprazole; pantoprazole; esomeprazole,    lansoprazole, and rabeprazole,-   wherein optionally the macrolide antibiotic is selected from the    group consisting of azithromycin, clarithromycin, erythromycin,    fidaxomicin, and telithromycin,-   wherein optionally the nitroimidazole antibiotic is selected from    the group consisting of metronidazole, tinidazole, and secnidazole,-   wherein optionally the ansamycin antibiotic is selected from the    group consisting of rifabutin, rifampicin, rifapentin, and    rifamixin.-   5. A method for treating or preventing Helicobacter pylori (H.    pylori) infection in an individual in need thereof, the method    comprising administering to the individual in need thereof a    therapeutic combination comprising-   (i) amoxicillin, vonoprazan, furazolidone, and rifabutin;-   (ii) amoxicillin, vonoprazan, bismuth, furazolidone, rifabutin;-   (iii) amoxicillin, vonoprazan, bismuth, levofloxacin, rifabutin;-   (iv) amoxicillin, vonoprazan, levofloxacin, rifabutin;-   (v) amoxicillin, vonoprazan, bismuth, levofloxacin, furazolidone,    rifabutin;-   (v) amoxicillin, vonoprazan, bismuth, tetracycline, rifabutin;-   (vi) metronidazole, vonoprazan, bismuth, tetracycline, rifabutin;-   (v) vonoprazan, bismuth, levofloxacin, rifabutin; or-   (vi) amoxicillin, vonoprazan, furazolidone, rifabutin, bismuth, and    nitazoxanide,-   wherein optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid.-   6. The method of any one of the preceding forms, wherein the    therapeutic combination is administered to the individual in need    thereof for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 or    more days.-   7. The method of any one of the preceding forms, wherein the    therapeutic combination is, is contained in or comprises a    formulation, a pharmaceutical preparation or a pharmaceutical    composition.-   8. The method of any one of the preceding forms, wherein the    vonoprazan or vonoprazan fumarate, or the    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or the    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is administered to the individual in    need thereof:

(a) at a unit dosage of between about 5 mg to about 200 mg per day, or

(b) in a unit dosage form of between about 10 mg and 200 mgm, or betweenabout between about 40 mg and 100 mgm, or is about 10, 20, 30, 40, 50,60, 70, 75, 80, 90 or 100 mg per unit dose,

which optionally can be administered once a day, bid or tid, or fourtimes a day, five times a day or six times a day or more, regimen.

-   9. The method of any one of the preceding forms, wherein therapeutic    combination, or the formulation, the pharmaceutical or the    pharmaceutical preparation, is formulated as a chewable delivery    vehicle, a gum, a gummy, a candy, a lozenge, an ice cream or an ice,    or a yogurt.-   10. The method of any one of the preceding forms, wherein    therapeutic combination, or the formulation, the pharmaceutical or    the pharmaceutical preparation, further comprises a flavoring or a    sweetening agent, an aspartamine, a stevia, monk fruit, a sucralose,    a saccharin, a cyclamate, a xylitol, a vanilla, an artificial    vanilla or chocolate or strawberry flavor, an artificial chocolate    essence, or a mixture or combination thereof.-   11. The method of any one of the preceding forms, wherein    therapeutic combination, or the formulation, the pharmaceutical or    the pharmaceutical preparation, further comprises a preservative, a    benzoic acid or a potassium sorbate.-   12. The method of any one of the preceding forms, wherein    therapeutic combination, or the formulation, the pharmaceutical or    the pharmaceutical preparation, further comprises, or has added to:    at least one probiotic or prebiotic, wherein optionally the    prebiotic comprises an inulin, lactulose, extracts of artichoke,    chicory root, oats, barley, various legumes, garlic, kale, beans or    flax or an herb, wherein optionally the probiotic comprises a    cultured or stool-extracted microorganism or bacteria, or a    bacterial component, and optionally the bacteria or bacterial    component comprises or is derived from a Saccharomyces boulardii,    Bacteroidetes, a Firmicutes, a Lactobacilli, a Bifidobacteria, an E.    coli, a Strep fecalis and equivalents.-   13. The method of any one of the preceding forms, wherein    therapeutic combination, or the formulation, the pharmaceutical or    the pharmaceutical preparation, further comprises, or has added to:    at least one congealing agent, wherein optionally the congealing    agent comprises an arrowroot or a plant starch, a powdered flour, a    powdered potato or potato starch, an absorbant polymer, an    Absorbable Modified Polymer, and/or a corn flour or a corn starch.-   14. The method of any one of the preceding forms, wherein    therapeutic combination, or the formulation, the pharmaceutical or    the pharmaceutical preparation, further comprises an additive    selected from one or more of a saline, a media, a defoaming agent, a    surfactant agent, a lubricant, an acid neutralizer, a marker, a cell    marker, a drug, an antibiotic, a contrast agent, a dispersal agent,    a buffer or a buffering agent, a sweetening agent, a debittering    agent, a flavoring agent, a pH stabilizer, an acidifying agent, a    preservative, a desweetening agent and/or coloring agent, vitamin,    mineral and/or dietary supplement, or a prebiotic nutrient.-   15. The method of any one of the preceding forms, wherein    therapeutic combination, or the formulation, the pharmaceutical or    the pharmaceutical preparation, further comprises, or has added to:    at least one Biofilm Disrupting Compound, wherein optionally the    biofilm disrupting compound comprises an enzyme, a deoxyribonuclease    (DNase), N-acetylcysteine, an auranofin, an alginate lyase,    glycoside hydrolase dispersin B; a Quorum-sensing inhibitor, a    ribonucleic acid III inhibiting peptide, Salvadora persica extracts,    Competence-stimulating peptide, Patulin and penicillic acid;    peptides—cathelicidin-derived peptides, small lytic peptide, PTP-7,    Nitric oxide, neo-emulsions; ozone, lytic bacteriophages,    lactoferrin, xylitol hydrogel, synthetic iron chelators, cranberry    components, curcumin, silver nanoparticles,    Acetyl-11-keto-β-boswellic acid (AKBA), barley coffee components,    probiotics, sinefungin, S-adenosylmethionine,    S-adenosyl-homocysteine, Delisea furanones, N-sulfonyl homoserine    lactones or any combination thereof.-   16. The method of any one of the preceding forms, wherein    therapeutic combination, or the formulation, the pharmaceutical or    the pharmaceutical preparation, further comprises, or has added to a    statin selected from the group consisting of atorvastatin,    fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin,    and simvastatin.-   17. The method of any one of the preceding forms, wherein    therapeutic combination, or the formulation, the pharmaceutical or    the pharmaceutical preparation, further comprises, or has added to    pronase.-   18. The method of any one of the preceding forms, wherein    therapeutic combination, or the formulation, the pharmaceutical or    the pharmaceutical preparation, is formulated as a delayed or    gradual enteric release composition or formulation, and optionally    the formulation comprises a gastro-resistant coating designed to    dissolve at a pH of 7 in the terminal ileum, e.g., an active    ingredient is coated with an acrylic based resin or equivalent,    e.g., a poly(meth)acrylate, e.g. a methacrylic acid copolymer B, NF,    which dissolves at pH 7 or greater, e.g., comprises a    multimatrix (MMX) formulation.-   19. The method of any one of the preceding forms, wherein    therapeutic combination, or the formulation, the pharmaceutical or    the pharmaceutical preparation, is contained in a delivery vehicle,    product of manufacture, container, syringe, device or bag.-   20. The method of any one of the preceding forms, wherein    therapeutic combination, or the formulation, the pharmaceutical or    the pharmaceutical preparation, is initially manufactured or    formulated as a liquid, a suspension, a gel, a geltab, a semisolid,    a tablet, a sachet, a lozenge or a capsule, or as an enteral    formulation, or re-formulated for final delivery as a liquid, a    suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a    lozenge or a capsule, or as an enteral formulation.-   21. A therapeutic combination comprising:

(a) a composition comprising or consisting of: vonoprazan or avonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™; and

(b) an antimicrobial or antibiotic drug or composition comprising orconsisting of:

-   (i)    -   (1) an amoxicillin, formulated for administration to the        individual in need thereof at a dose of between about 1 gram (g)        to about 2 g twice daily (bid), and optionally the amoxicillin        is formulated as amoxicillin/ clavulanic acid, also known as        co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™,        TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a clarithromycin, optionally BIAXIN™, formulated for        administration to the individual in need thereof at a dose of        between about 100 mg to about 2 g twice daily,    -   wherein the vonoprazan or a vonoprazan fumarate, or a        5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine        monofumarate, or a        1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine        fumarate), optionally TAKECAB™, is formulated for administration        to the individual in need thereof at a dose of between 20 mg to        about 50 mg twice daily (bid), or for about 25 mg or more twice        daily (bid);-   (ii)    -   (1) an amoxicillin, formulated for administration to the        individual in need thereof at a dose of between about 500 gm to        about 1 g three times daily (tid), and optionally the        amoxicillin is formulated as amoxicillin/clavulanic acid, also        known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,        AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a metronidazole, optionally FLAGYL™, METRO™, formulated for        administration to the individual in need thereof at a dose of        between about 200 mg to about 500 mg three times daily (tid),    -   wherein the vonoprazan or a vonoprazan fumarate, or a        5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine        monofumarate, or a        1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine        fumarate), optionally TAKECAB™, is formulated for administration        to the individual in need thereof at a dose of between 20 mg to        about 50 mg three times daily (tid), or for about 25 mg or more        three times daily (tid);-   (iii)    -   (1) an amoxicillin, formulated for administration to the        individual in need thereof at a dose of between about 250 gm to        about 1 g twice daily (bid) or three times daily (tid), and        optionally the amoxicillin is formulated as amoxicillin/        clavulanic acid, also known as co-amoxiclav, or is optionally        ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a rifabutin, optionally MYCOBUTIN™, formulated for        administration to the individual in need thereof at a dose of        between about 50 mg to about 250 mg twice daily (bid) or three        times daily (tid),    -   wherein the vonoprazan or a vonoprazan fumarate, or a        5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine        monofumarate, or a        1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine        fumarate), optionally TAKECAB™, is formulated for administration        to the individual in need thereof at a dose of between 5 mg to        about 200 mg or more twice daily (bid) or three times daily        (tid);-   (iv)    -   (1) an amoxicillin, formulated for administration to the        individual in need thereof at a dose of between about 250 gm to        about 1 g twice daily (bid) or three times daily (tid), and        optionally the amoxicillin is formulated as amoxicillin/        clavulanic acid, also known as co-amoxiclav, or is optionally        ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a levofloxacin, formulated for administration to the        individual in need thereof at a dose of between about 100 mg to        about 500 mg twice daily (bid) or three times daily (tid),    -   wherein the vonoprazan or a vonoprazan fumarate, or a        5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine        monofumarate, or a        1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine        fumarate), optionally TAKECAB™, is formulated for administration        to the individual in need thereof at a dose of between 5 mg to        about 200 mg or more twice daily (bid) or three times daily        (tid);-   (v)    -   (1) an amoxicillin, formulated for administration to the        individual in need thereof at a dose of between about 250 gm to        about 1 g twice daily (bid) or three times daily (tid), and        optionally the amoxicillin is formulated as amoxicillin/        clavulanic acid, also known as co-amoxiclav, or is optionally        ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a ciprofloxacin, optionally CILOXAN™, CIPRO™, NEOFLOXIN™        formulated for administration to the individual in need thereof        at a dose of between about 100 mg to about 500 mg twice daily        (bid) or three times daily (tid),    -   wherein the vonoprazan or a vonoprazan fumarate, or a        5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine        monofumarate, or a        1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine        fumarate), optionally TAKECAB™, is formulated for administration        to the individual in need thereof at a dose of between 5 mg to        about 200 mg or more twice daily (bid) or three times daily        (tid);-   (vi)    -   (1) an amoxicillin, formulated for administration to the        individual in need thereof at a dose of between about 250 gm to        about 1 g twice daily (bid) or three times daily (tid), and        optionally the amoxicillin is formulated as amoxicillin/        clavulanic acid, also known as co-amoxiclav, or is optionally        ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a moxifloxacin, optionally AVELOX™, VIGAMOX™, MOXEZA™        formulated for administration to the individual in need thereof        at a dose of between about 25 mg to about 500 mg per day,    -   wherein the vonoprazan or a vonoprazan fumarate, or a        5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine        monofumarate, or a        1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine        fumarate), optionally TAKECAB™, is formulated for administration        to the individual in need thereof at a dose of between 5 mg to        about 200 mg or more twice daily (bid) or three times daily        (tid);-   (vii)    -   (1) an amoxicillin, a clarithromycin, a metronidazole, a        levofloxacin, a ciprofloxacin or a moxifloxacin, formulated for        administration to the individual in need thereof at a dose as        set forth in any of steps (i) to (vi), and optionally the        amoxicillin is formulated as amoxicillin/ clavulanic acid, also        known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,        AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a TG44, or a 1-1000 mg/d] {[4-methylbenzyl        4′-[trans-4-(guanidine-methyl) cyclohexyl        carbonyloxy]biphenyl-4-carboxylate monohydrochloride}, or CAS        registry number 178748-55-5, formulated for administration to        the individual in need thereof at a dose of between about 15 mg        to about 50 mg per day, or at about 50 to 500 mg per day,    -   wherein the vonoprazan or a vonoprazan fumarate, or a        5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine        monofumarate, or a        1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine        fumarate), optionally TAKECAB™, is formulated for administration        to the individual in need thereof at a dose of between 5 mg to        about 50 mg, or 20 mg or more, twice daily (bid) or three times        daily (tid);-   (viii)    -   (1) an amoxicillin,    -   (2) a furazolidone, optionally FUROXONE™, DEPENDAL-M™,        formulated for administration to the individual in need thereof        at a dose of between about 50 to about 600 mg/d, and    -   (3) a rifabutin, optionally MYCOBUTIN™, formulated for        administration to the individual in need thereof at a dose of        between about 60 to about 450 mg/d, and optionally the rifabutin        dose is ramped up starting at about 40 to about 60 g bid or tid,        and optionally rising over 3 days to about 200 to about 450/d,    -   wherein the vonoprazan or a vonoprazan fumarate, or a        5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine        monofumarate, or a        1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine        fumarate), optionally TAKECAB™, is formulated for administration        to the individual in need thereof at a dose as set forth in any        of (i) to (vii);-   (ix) a therapeutic combination as set forth in Table 1; or-   (x) any combination of (i) to (ix).-   22. A kit or product of manufacture comprising a therapeutic    combination of form 21, or a therapeutic combination of any of the    preceding forms.-   23. Use of a therapeutic combination of form 21, or a therapeutic    combination of any of the preceding forms, or a kit or product of    manufacture of form 22, in the manufacture of a medicament.-   24. A therapeutic combination as set forth in any one of the    preceding forms for use in treating, ameliorating, reversing and/or    preventing (acting as a prophylaxis) a Helicobacter pylori (H.    pylori) infection in an individual in need thereof.

In a second aspect, forms of the invention described herein include thefollowing:

-   1. Use of:

(a) a composition comprising or consisting of: vonoprazan or avonoprazan fumarate, or a 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine monofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™; and

(b) an antimicrobial or antibiotic drug or composition comprising orconsisting of:

(i)

-   -   (1) an amoxicillin, formulated for administration at a dose of        between about 1 gram (g) to about 2 g twice daily (bid),        optionally the amoxicillin is formulated as amoxicillin/        clavulanic acid, also known as co-amoxiclav, or is optionally        ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a clarithromycin, optionally BIAXIN™, formulated for        administration at a dose of between about 100 mg to about 2 g        twice daily,

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration at adose of between 20 mg to about 50 mg twice daily (bid), or for about 25mg or more twice daily (bid);

(ii)

-   -   (1) an amoxicillin, formulated for administration at a dose of        between about 500 gm to about 1 g three times daily (tid), and        optionally the amoxicillin is formulated as amoxicillin/        clavulanic acid, also known as co-amoxiclav, or is optionally        ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a metronidazole, optionally FLAGYL™, METRO™, formulated for        administration at a dose of between about 200 mg to about 500 mg        three times daily (tid),

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration at adose of between 20 mg to about 50 mg three times daily (tid), or forabout 25 mg or more three times daily (tid);

(iii)

-   -   (1) an amoxicillin, formulated for administration at a dose of        between about 250 gm to about 1 g twice daily (bid) or three        times daily (tid), and optionally the amoxicillin is formulated        as amoxicillin/ clavulanic acid, also known as co-amoxiclav, or        is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™,        TRIMOX™; and    -   (2) a rifabutin, optionally MYCOBUTIN™, formulated for        administration at a dose of between about 50 mg to about 250 mg        twice daily (bid) or three times daily (tid),

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration at adose of between 5 mg to about 200 mg or more twice daily (bid) or threetimes daily (tid);

(iv)

-   -   (1) an amoxicillin, formulated for administration at a dose of        between about 250 gm to about 1 g twice daily (bid) or three        times daily (tid), and optionally the amoxicillin is formulated        as amoxicillin/ clavulanic acid, also known as co-amoxiclav, or        is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™,        TRIMOX™; and    -   (2) a levofloxacin, formulated for administration at a dose of        between about 100 mg to about 500 mg twice daily (bid) or three        times daily (tid),

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration at adose of between 5 mg to about 200 mg or more twice daily (bid) or threetimes daily (tid);

(v)

-   -   (1) an amoxicillin, formulated for administration at a dose of        between about 250 gm to about 1 g twice daily (bid) or three        times daily (tid), and optionally the amoxicillin is formulated        as amoxicillin/ clavulanic acid, also known as co-amoxiclav, or        is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™,        TRIMOX™; and    -   (2) a ciprofloxacin, optionally CILOXAN™, CIPRO™, NEOFLOXIN™        administered to the individual in need thereof at a dose of        between about 100 mg to about 500 mg twice daily (bid) or three        times daily (tid),

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 200 mg or more twicedaily (bid) or three times daily (tid);

(vi)

-   -   (1) an amoxicillin, administered to the individual in need        thereof at a dose of between about 250 gm to about 1 g twice        daily (bid) or three times daily (tid), and optionally the        amoxicillin is formulated as amoxicillin/clavulanic acid, also        known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,        AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a moxifloxacin, optionally AVELOX™, VIGAMOX™, MOXEZA™        administered to the individual in need thereof at a dose of        between about 25 mg to about 500 mg per day,

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 200 mg or more twicedaily (bid) or three times daily (tid);

(vii)

-   -   (1) an amoxicillin, a clarithromycin, a metronidazole, a        levofloxacin, a ciprofloxacin or a moxifloxacin, administered to        the individual in need thereof at a dose as set forth in any of        steps (i) to (vi), optionally the amoxicillin is formulated as        amoxicillin/ clavulanic acid, also known as co-amoxiclav, or is        optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™,        TRIMOX™; and    -   (2) a TG44, or a 1-1000 mg/d] {[4-methylbenzyl        4′-[trans-4-(guanidine-methyl) cyclohexyl        carbonyloxy]biphenyl-4-carboxylate monohydrochloride}, or CAS        registry number 178748-55-5, administered to the individual in        need thereof at a dose of between about 15 mg to about 50 mg per        day, or at about 50 to 500 mg per day,

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine monofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 50 mg, or 20 mg or more,twice daily (bid) or three times daily (tid);

(viii)

-   -   (1) an amoxicillin,    -   (2) a furazolidone, optionally FUROXONE™, DEPENDAL-M™,        administered to the individual in need thereof at a dose of        between about 50 to about 600 mg/d, and    -   (3) a rifabutin, optionally MYCOBUTIN™, administered to the        individual in need thereof at a dose of between about 60 to        about 450 mg/d, and optionally the rifabutin dose is ramped up        starting at about 40 to about 60 g bid or tid, and optionally        rising over 3 days to about 200 to about 450/d,

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine monofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose as set forth in any of (i) to (vii);

(ix) a therapeutic combination as set forth in Table 1; or

(x) any combination of (i) to (ix),

in the manufacture of a medicament for treating or preventingHelicobacter pylori (H. pylori) infection in an individual in needthereof.

-   2. Use of a therapeutic combination comprising:-   (a) vonoprazan, and-   (b) a prolonged release formulation of an antibiotic comprising:-   (1) amoxicillin wherein optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, and/or-   (2) an antibiotic selected from the group consisting of    clarithromycin, azithromycin, roxithromycin and erythromycin,    in the manufacture of a medicament for treating or preventing    Helicobacter pylori (H. pylori) infection in an individual in need    thereof,-   wherein the vonoprazan is formulated for administration in an amount    of 10 mg to 1 g per day, and the amoxicillin is formulated for    administration in an amount of 10 mg to 6 g per day.-   3. Use of a therapeutic combination comprising-   (a) a prolonged release microencapsulated and/or multimatrix    formulation of vonoprazan, and-   (b) a prolonged release microencapsulated and/or multimatrix    formulation of amoxicillin wherein optionally the amoxicillin is    formulated as amoxicillin/clavulanic acid, or-   (c) a prolonged release microencapsulated and/or multimatrix    formulation of vonoprazan and amoxicillin wherein optionally the    amoxicillin is formulated as amoxicillin/clavulanic acid,    in the manufacture of a medicament for treating or preventing    Helicobacter pylori (H. pylori) infection in an individual in need    thereof,-   wherein the vonoprazan is administered in an amount of 10 mg to 1 g    per day, and the amoxicillin is administered in an amount of 1 g to    6 g per day.-   4. Use of a therapeutic combination comprising:-   (a) vonoprazan,-   (b) a proton pump inhibitor, and-   (c) at least one antibiotic selected from the group consisting of    amoxicillin, wherein optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, ampicillin, pivampicillin, hetacillin,    bacampicillin, metampicillin, talampicillin, epicillin, a macrolide    antibiotic, furazolidone, ciprofloxacin, levofloxacin, tetracycline,    a nitroimidazole antibiotic, bismuth, an ansamycin antibiotic, and    nitazoxanide,-   wherein optionally the proton pump inhibitor is selected from the    group consisting of omeprazole; pantoprazole; esomeprazole,    lansoprazole, and rabeprazole,-   wherein optionally the macrolide antibiotic is selected from the    group consisting of azithromycin, clarithromycin, erythromycin,    fidaxomicin, and telithromycin,-   wherein optionally the nitroimidazole antibiotic is selected from    the group consisting of metronidazole, tinidazole, and secnidazole,-   wherein optionally the ansamycin antibiotic is selected from the    group consisting of rifabutin, rifampicin, rifapentin, and    rifamixin,    in the manufacture of a medicament for treating or preventing    Helicobacter pylori (H. pylori) infection in an individual in need    thereof.-   5. Use of a therapeutic combination comprising-   (i) amoxicillin, vonoprazan, furazolidone, and rifabutin;-   (ii) amoxicillin, vonoprazan, bismuth, furazolidone, rifabutin;-   (iii) amoxicillin, vonoprazan, bismuth, levofloxacin, rifabutin;-   (iv) amoxicillin, vonoprazan, levofloxacin, rifabutin;-   (v) amoxicillin, vonoprazan, bismuth, levofloxacin, furazolidone,    rifabutin;-   (v) amoxicillin, vonoprazan, bismuth, tetracycline, rifabutin;-   (vi) metronidazole, vonoprazan, bismuth, tetracycline, rifabutin;-   (v) vonoprazan, bismuth, levofloxacin, rifabutin; or-   (vi) amoxicillin, vonoprazan, furazolidone, rifabutin, bismuth, and    nitazoxanide,-   wherein optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, in the manufacture of a medicament for    treating or preventing Helicobacter pylori (H. pylori) infection in    an individual in need thereof.-   6. The use of any one of the preceding forms, wherein the    therapeutic combination is formulated for administration to the    individual in need thereof for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,    12, 13 or 14 or more days.-   7. The use of any one of the preceding forms, wherein the    therapeutic combination is, is contained in or comprises a    formulation, a pharmaceutical preparation or a pharmaceutical    composition.-   8. The use of any of the preceding forms, wherein the vonoprazan or    vonoprazan fumarate, or the    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or the    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is formulated for administration:

(a) at a unit dosage of between about 5 mg to about 200 mg per day, or

(b) in a unit dosage form of between about 10 mg and 200 mgm, or betweenabout between about 40 mg and 100 mgm, or is about 10, 20, 30, 40, 50,60, 70, 75, 80, 90 or 100 mg per unit dose,

which optionally is formulated for administration once a day, bid ortid, or a four times a day, five times a day or six times a day or more.

-   9. The use of any of the preceding forms, wherein therapeutic    combination, or the formulation, the pharmaceutical or the    pharmaceutical preparation, is formulated as a chewable delivery    vehicle, a gum, a gummy, a candy, a lozenge, an ice cream or an ice,    or a yogurt.-   10. The use of any of the preceding forms, wherein the medicament    further comprises a flavoring or a sweetening agent, an aspartamine,    a stevia, monk fruit, a sucralose, a saccharin, a cyclamate, a    xylitol, a vanilla, an artificial vanilla or chocolate or strawberry    flavor, an artificial chocolate essence, or a mixture or combination    thereof.-   11. The use of any of the preceding forms, wherein the medicament    further comprises a preservative, a benzoic acid or a potassium    sorbate.-   12. The use of any of the preceding forms, wherein the medicament    further comprises at least one probiotic or prebiotic, wherein    optionally the prebiotic comprises an inulin, lactulose, extracts of    artichoke, chicory root, oats, barley, various legumes, garlic,    kale, beans or flacks or an herb, wherein optionally the probiotic    comprises a cultured or stool-extracted microorganism or bacteria,    or a bacterial component, and optionally the bacteria or bacterial    component comprises or is derived from a Bacteroidetes, a    Firmicutes, a Lactobacilli, a Bifidobacteria, an E. coli, a Strep    fecalis and equivalents.-   13. The use of any of the preceding forms, wherein the medicament    further comprises at least one congealing agent, wherein optionally    the congealing agent comprises an arrowroot or a plant starch, a    powdered flour, a powdered potato or potato starch, an absorbant    polymer, an Absorbable Modified Polymer, and/or a corn flour or a    corn starch.-   14. The use of any of the preceding forms, wherein the medicament    further comprises an additive selected from one or more of a saline,    a media, a defoaming agent, a surfactant agent, a lubricant, an acid    neutralizer, a marker, a cell marker, a drug, an antibiotic, a    contrast agent, a dispersal agent, a buffer or a buffering agent, a    sweetening agent, a debittering agent, a flavoring agent, a pH    stabilizer, an acidifying agent, a preservative, a desweetening    agent and/or coloring agent, vitamin, mineral and/or dietary    supplement, or a prebiotic nutrient.-   15. The use of any of the preceding forms, wherein the medicament    further comprises at least one Biofilm Disrupting Compound, wherein    optionally the biofilm disrupting compound comprises an enzyme, a    deoxyribonuclease (DNase), N-acetylcysteine, an auranofin, an    alginate lyase, glycoside hydrolase dispersin B; a Quorum-sensing    inhibitor, a ribonucleic acid III inhibiting peptide, Salvadora    persica extracts, Competence-stimulating peptide, Patulin and    penicillic acid; peptides—cathelicidin-derived peptides, small lytic    peptide, PTP-7, Nitric oxide, neo-emulsions; ozone, lytic    bacteriophages, lactoferrin, xylitol hydrogel, synthetic iron    chelators, cranberry components, curcumin, silver nanoparticles,    Acetyl-11-keto-β-boswellic acid (AKBA), barley coffee components,    probiotics, sinefungin, S-adenosylmethionine,    S-adenosyl-homocysteine, Delisea furanones, N-sulfonyl homoserine    lactones or any combination thereof.-   16. The use of any of the preceding forms, wherein the medicament is    formulated as a delayed or gradual enteric release composition or    formulation, and optionally the formulation comprises a    gastro-resistant coating designed to dissolve at a pH of 7 in the    terminal ileum, e.g., an active ingredient is coated with an acrylic    based resin or equivalent, e.g., a poly(meth)acrylate, e.g. a    methacrylic acid copolymer B, NF, which dissolves at pH 7 or    greater, e.g., comprises a multimatrix (MMX) formulation.-   17. The use of any of the preceding forms, wherein the medicament is    contained in a delivery vehicle, product of manufacture, container,    syringe, device or bag.-   18. The use of any of the preceding forms, wherein the medicament is    initially manufactured or formulated as a liquid, a suspension, a    gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or a    capsule, or as an enteral formulation, or re-formulated for final    delivery as a liquid, a suspension, a gel, a geltab, a semisolid, a    tablet, a sachet, a lozenge or a capsule, or as an enteral    formulation.-   19. The use of any one of the preceding forms, wherein therapeutic    combination, or the formulation, the pharmaceutical or the    pharmaceutical preparation, further comprises, or has added to a    statin selected from the group consisting of atorvastatin,    fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin,    and simvastatin.-   20. The use of any one of the preceding forms, wherein therapeutic    combination, or the formulation, the pharmaceutical or the    pharmaceutical preparation, further comprises, or has added to    pronase.

In a third aspect, forms of the invention described herein include thefollowing:

-   1. A combination of:

(a) a composition comprising or consisting of: vonoprazan or avonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™; and

(b) an antimicrobial or antibiotic drug or composition comprising orconsisting of:

(i)

-   -   (1) an amoxicillin, formulated for administration at a dose of        between about 1 gram (g) to about 2 g twice daily (bid),        optionally the amoxicillin is formulated as amoxicillin/        clavulanic acid, also known as co-amoxiclav, or is optionally        ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a clarithromycin, optionally BIAXIN™, formulated for        administration at a dose of between about 100 mg to about 2 g        twice daily,

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration at adose of between 20 mg to about 50 mg twice daily (bid), or for about 25mg or more twice daily (bid);

(ii)

-   -   (1) an amoxicillin, formulated for administration at a dose of        between about 500 gm to about 1 g three times daily (tid), and        optionally the amoxicillin is formulated as amoxicillin/        clavulanic acid, also known as co-amoxiclav, or is optionally        ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a metronidazole, optionally FLAGYL™, METRO™, formulated for        administration at a dose of between about 200 mg to about 500 mg        three times daily (tid),

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration at adose of between 20 mg to about 50 mg three times daily (tid), or forabout 25 mg or more three times daily (tid);

(iii)

-   -   (1) an amoxicillin, formulated for administration at a dose of        between about 250 gm to about 1 g twice daily (bid) or three        times daily (tid), and optionally the amoxicillin is formulated        as amoxicillin/ clavulanic acid, also known as co-amoxiclav, or        is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™,        TRIMOX™; and    -   (2) a rifabutin, optionally MYCOBUTIN™, formulated for        administration at a dose of between about 50 mg to about 250 mg        twice daily (bid) or three times daily (tid),

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration at adose of between 5 mg to about 200 mg or more twice daily (bid) or threetimes daily (tid);

(iv)

-   -   (1) an amoxicillin, formulated for administration at a dose of        between about 250 gm to about 1 g twice daily (bid) or three        times daily (tid), and optionally the amoxicillin is formulated        as amoxicillin/ clavulanic acid, also known as co-amoxiclav, or        is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™,        TRIMOX™; and    -   (2) a levofloxacin, formulated for administration at a dose of        between about 100 mg to about 500 mg twice daily (bid) or three        times daily (tid),

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration at adose of between 5 mg to about 200 mg or more twice daily (bid) or threetimes daily (tid);

(v)

-   -   (1) an amoxicillin, formulated for administration at a dose of        between about 250 gm to about 1 g twice daily (bid) or three        times daily (tid), and optionally the amoxicillin is formulated        as amoxicillin/ clavulanic acid, also known as co-amoxiclav, or        is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™,        TRIMOX™; and    -   (2) a ciprofloxacin, optionally CILOXAN™, CIPRO™, NEOFLOXIN™        administered to the individual in need thereof at a dose of        between about 100 mg to about 500 mg twice daily (bid) or three        times daily (tid),

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrool-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 200 mg or more twicedaily (bid) or three times daily (tid);

(vi)

-   -   (1) an amoxicillin, administered to the individual in need        thereof at a dose of between about 250 gm to about 1 g twice        daily (bid) or three times daily (tid), and optionally the        amoxicillin is formulated as amoxicillin/clavulanic acid, also        known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,        AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and    -   (2) a moxifloxacin, optionally AVELOX™, VIGAMOX™, MOXEZA™        administered to the individual in need thereof at a dose of        between about 25 mg to about 500 mg per day,

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 200 mg or more twicedaily (bid) or three times daily (tid);

(vii)

-   -   (1) an amoxicillin, a clarithromycin, a metronidazole, a        levofloxacin, a ciprofloxacin or a moxifloxacin, administered to        the individual in need thereof at a dose as set forth in any of        steps (i) to (vi), optionally the amoxicillin is formulated as        amoxicillin/ clavulanic acid, also known as co-amoxiclav, or is        optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™,        TRIMOX™; and    -   (2) a TG44, or a 1-1000 mg/d] {[4-methylbenzyl        4′-[trans-4-(guanidine-methyl) cyclohexyl        carbonyloxy]biphenyl-4-carboxylate monohydrochloride}, or CAS        registry number 178748-55-5, administered to the individual in        need thereof at a dose of between about 15 mg to about 50 mg per        day, or at about 50 to 500 mg per day,

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 50 mg, or 20 mg or more,twice daily (bid) or three times daily (tid);

(viii)

-   -   (1) an amoxicillin,    -   (2) a furazolidone, optionally FUROXONE™, DEPENDAL-M™,        administered to the individual in need thereof at a dose of        between about 50 to about 600 mg/d, and    -   (3) a rifabutin, optionally MYCOBUTIN™, administered to the        individual in need thereof at a dose of between about 60 to        about 450 mg/d, and optionally the rifabutin dose is ramped up        starting at about 40 to about 60 g bid or tid, and optionally        rising over 3 days to about 200 to about 450/d,

wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose as set forth in any of (i) to (vii);

(ix) a therapeutic combination as set forth in Table 1; or

(x) any combination of (i) to (ix),

for use in treating or preventing Helicobacter pylori (H. pylori)infection in an individual in need thereof.

-   2. A therapeutic combination comprising:-   (a) vonoprazan, and-   (b) a prolonged release formulation of an antibiotic comprising:-   (1) amoxicillin wherein optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, and/or-   (2) an antibiotic selected from the group consisting of    clarithromycin, azithromycin, roxithromycin and erythromycin,-   wherein the vonoprazan is formulated for administration in an amount    of 10 mg to 1 g per day, and the amoxicillin is formulated for    administration in an amount of 10 mg to 6 g per day,-   for use in treating or preventing Helicobacter pylori (H. pylori)    infection in an individual in need thereof.-   3. A therapeutic combination comprising:-   (a) a prolonged release microencapsulated and/or multimatrix    formulation of vonoprazan, and-   (b) a prolonged release microencapsulated and/or multimatrix    formulation of amoxicillin wherein optionally the amoxicillin is    formulated as amoxicillin/clavulanic acid, or-   (c) a prolonged release microencapsulated and/or multimatrix    formulation of vonoprazan and amoxicillin wherein optionally the    amoxicillin is formulated as amoxicillin/clavulanic acid,-   wherein the vonoprazan is formulated for administration in an amount    of 10 mg to 1 g per day, and the amoxicillin is formulated for    administration in an amount of 1 g to 6 g per day,-   for use in treating or preventing Helicobacter pylori (H. pylori)    infection in an individual in need thereof.-   4. A therapeutic combination comprising:-   (a) vonoprazan,-   (b) a proton pump inhibitor, and-   (c) at least one antibiotic selected from the group consisting of    amoxicillin, wherein optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid, ampicillin, pivampicillin, hetacillin,    bacampicillin, metampicillin, talampicillin, epicillin, a macrolide    antibiotic, furazolidone, ciprofloxacin, levofloxacin, tetracycline,    a nitroimidazole antibiotic, bismuth, an ansamycin antibiotic, and    nitazoxanide,-   wherein optionally the proton pump inhibitor is selected from the    group consisting of omeprazole; pantoprazole; esomeprazole,    lansoprazole, and rabeprazole,-   wherein optionally the macrolide antibiotic is selected from the    group consisting of azithromycin, clarithromycin, erythromycin,    fidaxomicin, and telithromycin,-   wherein optionally the nitroimidazole antibiotic is selected from    the group consisting of metronidazole, tinidazole, and secnidazole,-   wherein optionally the ansamycin antibiotic is selected from the    group consisting of rifabutin, rifampicin, rifapentin, and    rifamixin,-   for use in treating or preventing Helicobacter pylori (H. pylori)    infection in an individual in need thereof.-   5. A therapeutic combination comprising-   (i) amoxicillin, vonoprazan, furazolidone, and rifabutin;-   (ii) amoxicillin, vonoprazan, bismuth, furazolidone, rifabutin;-   (iii) amoxicillin, vonoprazan, bismuth, levofloxacin, rifabutin;-   (iv) amoxicillin, vonoprazan, levofloxacin, rifabutin;-   (v) amoxicillin, vonoprazan, bismuth, levofloxacin, furazolidone,    rifabutin;-   (v) amoxicillin, vonoprazan, bismuth, tetracycline, rifabutin;-   (vi) metronidazole, vonoprazan, bismuth, tetracycline, rifabutin;-   (v) vonoprazan, bismuth, levofloxacin, rifabutin; or-   (vi) amoxicillin, vonoprazan, furazolidone, rifabutin, bismuth, and    nitazoxanide,-   wherein optionally the amoxicillin is formulated as    amoxicillin/clavulanic acid,-   for use in treating or preventing Helicobacter pylori (H. pylori)    infection in an individual in need thereof.-   6. The combination of any one of the preceding forms, wherein the    therapeutic combination is formulated for administration to the    individual in need thereof for about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,    12, 13 or 14 or more days.-   7. The combination of any one of the preceding forms, wherein the    therapeutic combination is, is contained in or comprises a    formulation, a pharmaceutical preparation or a pharmaceutical    composition.-   8. The combination of any of the preceding forms, wherein the    vonoprazan or vonoprazan fumarate, or the    5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine    monofumarate, or the    1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanamine    fumarate), optionally TAKECAB™, is formulated for administration:

(a) at a unit dosage of between about 5 mg to about 200 mg per day, or

(b) in a unit dosage form of between about 10 mg and 200 mgm, or betweenabout between about 40 mg and 100 mgm, or is about 10, 20, 30, 40, 50,60, 70, 75, 80, 90 or 100 mg per unit dose,

which optionally is formulated for administration once a day, bid ortid, or a four times a day, five times a day or six times a day or more.

-   9. The combination of any of the preceding forms, formulated as a    chewable delivery vehicle, a gum, a gummy, a candy, a lozenge, an    ice cream or an ice, or a yogurt.-   10. The combination of any of the preceding forms, further    comprising a flavoring or a sweetening agent, an aspartamine, a    stevia, monk fruit, a sucralose, a saccharin, a cyclamate, a    xylitol, a vanilla, an artificial vanilla or chocolate or strawberry    flavor, an artificial chocolate essence, or a mixture or combination    thereof.-   11. The combination of any of the preceding forms, further    comprising a preservative, a benzoic acid or a potassium sorbate.-   12. The combination of any of the preceding forms, further    comprising at least one probiotic or prebiotic, wherein optionally    the prebiotic comprises an inulin, lactulose, extracts of artichoke,    chicory root, oats, barley, various legumes, garlic, kale, beans or    flacks or an herb, wherein optionally the probiotic comprises a    cultured or stool-extracted microorganism or bacteria, or a    bacterial component, and optionally the bacteria or bacterial    component comprises or is derived from a Bacteroidetes, a    Firmicutes, a Lactobacilli, a Bifidobacteria, an E. coli, a Strep    fecalis and equivalents.-   13. The combination of any of the preceding forms, further    comprising at least one congealing agent, wherein optionally the    congealing agent comprises an arrowroot or a plant starch, a    powdered flour, a powdered potato or potato starch, an absorbant    polymer, an Absorbable Modified Polymer, and/or a corn flour or a    corn starch.-   14. The combination of any of the preceding forms, further    comprising an additive selected from one or more of a saline, a    media, a defoaming agent, a surfactant agent, a lubricant, an acid    neutralizer, a marker, a cell marker, a drug, an antibiotic, a    contrast agent, a dispersal agent, a buffer or a buffering agent, a    sweetening agent, a debittering agent, a flavoring agent, a pH    stabilizer, an acidifying agent, a preservative, a desweetening    agent and/or coloring agent, vitamin, mineral and/or dietary    supplement, or a prebiotic nutrient.-   15. The combination of any of the preceding forms, further    comprising at least one Biofilm Disrupting Compound, wherein    optionally the biofilm disrupting compound comprises an enzyme, a    deoxyribonuclease (DNase), N-acetylcysteine, an auranofin, an    alginate lyase, glycoside hydrolase dispersin B; a Quorum-sensing    inhibitor, a ribonucleic acid III inhibiting peptide, Salvadora    persica extracts, Competence-stimulating peptide, Patulin and    penicillic acid; peptides—cathelicidin-derived peptides, small lytic    peptide, PTP-7, Nitric oxide, neo-emulsions; ozone, lytic    bacteriophages, lactoferrin, xylitol hydrogel, synthetic iron    chelators, cranberry components, curcumin, silver nanoparticles,    Acetyl-11-keto-β-boswellic acid (AKBA), barley coffee components,    probiotics, sinefungin, S-adenosylmethionine,    S-adenosyl-homocysteine, Delisea furanones, N-sulfonyl homoserine    lactones or any combination thereof.-   16. The combination of any of the preceding forms, formulated as a    delayed or gradual enteric release composition or formulation, and    optionally the formulation comprises a gastro-resistant coating    designed to dissolve at a pH of 7 in the terminal ileum, e.g., an    active ingredient is coated with an acrylic based resin or    equivalent, e.g., a poly(meth)acrylate, e.g. a methacrylic acid    copolymer B, NF, which dissolves at pH 7 or greater, e.g., comprises    a multimatrix (MMX) formulation.-   17. The combination of any of the preceding forms, contained in a    delivery vehicle, product of manufacture, container, syringe, device    or bag.-   18. The combination of any of the preceding forms, wherein the    combination is initially manufactured or formulated as a liquid, a    suspension, a gel, a geltab, a semisolid, a tablet, a sachet, a    lozenge or a capsule, or as an enteral formulation, or re-formulated    for final delivery as a liquid, a suspension, a gel, a geltab, a    semisolid, a tablet, a sachet, a lozenge or a capsule, or as an    enteral formulation.

DETAILED DESCRIPTION

In alternative embodiments, provided are therapeutic combinations(including formulations, pharmaceutical preparations or pharmaceuticalcompositions) for treating, ameliorating, reversing and/or preventing(acting as a prophylaxis) a Helicobacter pylori (H. pylori) infection inan individual in need thereof, including products of manufacture andkits, for practicing methods as provided herein.

In alternative embodiments, therapeutic combinations, formulations,pharmaceutical preparations or pharmaceutical compositions as providedherein use vonoprazan to improve efficacy in novel combinations toachieve close to 100% eradication of Helicobacter pylori (H. pylori)infections; and this significant breakthrough is particularly relevantfor those individuals in need thereof who have previously failederadication of H. pylori, or at least have failed to get any orclinically sufficient resolution of an H. pylori infection and/orsymptoms associated with H. pylori infection.

In alternative embodiments, therapeutic combinations, formulations,pharmaceutical preparations or pharmaceutical compositions as providedherein use the unexpected bactericidal activity of the new compositionsmitigating resistance which give new life to otherwise failing oflagging H. pylori (HP)-eradication protocols, as discussed above. Byadding vonoprazan the resistance of H. pylori is clearly reduced, andwhile the invention is not limited by any particular mechanism ofaction, this may be due to vonoprazan causing a much greateravailability of amoxicillin in the stomach, leading to much highereradication rates across numerous trials, some reaching nearly 100%eradication. Additionally, vonoprozan itself has some endogenousanti-microbial activity.

In alternative embodiments, provided are therapeutic combinations(including formulations, pharmaceutical preparations or pharmaceuticalcompositions) which use vonoprazan in a dose of between about 5 mg toabout 200 mg per day, in conjunction with various other antibiotics orother antimicrobials or drugs.

In alternative embodiments, provided are therapeutic combinations(including formulations, pharmaceutical preparations or pharmaceuticalcompositions) which are more effective than the standard amoxicillin,clarithromycin, and vonoprazan protocol. In alternative embodiments,provided are therapeutic combinations and regimens comprising orconsisting of an amoxicillin, clarithromycin, and vonoprazan thatachieve significantly higher eradication than existing protocols, whereexemplary therapeutic combinations and drug regimens comprise, forexample:

amoxicillin is used at a dose of about 1 g to about 2 g twice daily, inconjunction with clarithromycin at about 100 mg through to about 2 gtwice daily, with vonoprazan at a dose of about 25 mg or more twicedaily, for about 5 or more days. Another combination is the use ofamoxicillin and clarithromycin in doses listed above but administered 3times daily and vonoprazan also 3 times daily, in doses between about 5mg to about 200 mg three times daily for 5 or more days;

a 7 day, or 5 or more days, course of vonoprazan at about 20 mg or morethree times daily, metronidazole at about 200 to about 500 mg threetimes daily and amoxicillin at about 500 mg to about 1 g three timesdaily, which can achieve close to 100% eradiation rate in those peoplewho are not allergic to amoxicillin or metronidazole given for 5 or moredays; this can be used as First Line or subsequent therapy composition;

vonoprazan 2 to 3 times daily in doses of about 5 mg to about 200 mg/d,together with rifabutin 2 to 3 times daily at about 50 mg to about 250mg, and amoxicillin at about 250 mg to about 1 g 2 to 3 times daily;this is also a very effective First Line or salvage/rescue therapy inthose patients who have previously failed eradication;

a combination taken for 5 or more days, is that of similar doses asgiven above of amoxicillin and vonoprazan but also combined with eitherlevofloxacin from between 100 to 500 mg 2 to 3 times per day orciprofloxacin at about 100 to about 500 mg 2 to 3 times/day (d), ormoxifloxacin at about 25 to about 500 mg/d;

vonoprazan at about 20 mg or more 2 to 3 times/day combined with the newanti HP agent TG44 (1-1000 mg/d] {[4-methylbenzyl4′-[trans-4-(guanidinomethyl) cyclohexylcarbonyloxy]biphenyl-4-carboxylate monohydrochloride} [CAS registrynumber 178748-55-5] twice or three times daily and the protocol caninclude the following: TG44 can be used alone with vonoprazan, orcombined with amoxycillin, clarithromycin, metronidazole, levofloxacin,ciprofloxacin or moxifloxacin in the doses given above, optionally forabout 5 or more days.

Additional exemplary therapeutic combinations that can be used 2 to 3times/d protocols, optionally taken for 5 or more days, include:

amoxicillin and vanoprazan, with furazolidone at about 50 to about 600mg/d, and rifabutin at about 60 to about 450 mg/d; the rifabutin dosecan be ramped up to prevent fevers, for example, starting at about 40 toabout 60 g bid or tid, and optionally rising over 3 days to about 200 toabout 450/d;

additional exemplary therapeutic combinations that can be used 2 to 3times/d protocols, optionally taken for 5 or more days, include those asset forth in Table 1, below:

TABLE 1 A. Amoxicillin Vonoprazan Furazolidone Rifabutin Times 375 mg 20mg 100 mg 60 mg DAY 1 8 am 4 Capsules 1 Capsule 1 Capsule 1 Capsule 1 pm4 Capsules 1 Capsule 1 Capsule 0 8 pm 4 Capsules 1 Capsule 1 Capsule 1Capsule DAY 2 8 am 4 Capsules 1 Capsule 1 Capsule 1 Capsule 1 pm 4Capsules 1 Capsule 1 Capsule 0 8 pm 4 Capsules 1 Capsule 1 Capsule  2Capsules DAY 3 TO DAY 14 Amoxicillin Vonoprazan Furazolidone RifabutinTimes 375 mg 20 mg 100 mg 120 mg 8 am 4 Capsules 1 Capsule 1 Capsule 1Capsule 1 pm 4 Capsules 1 Capsule 1 Capsule 0 8 pm 4 Capsules 1 Capsule1 Capsule 1 Capsule B. Amoxicillin Vonoprazan Bismuth FurazolidoneRifabutin Times 375 mg 20 mg 300 mg 100 mg 60 mg DAY 1 8 am 4 Capsules 1Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4 Capsules 1 Capsule 2Capsules 1 Capsule 0 8 pm 4 Capsules 1 Capsule 2 Capsules 1 Capsule 1Capsule DAY 2 8 am 4 Capsules 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1pm 4 Capsules 1 Capsule 2 Capsules 1 Capsule 0 8 pm 4 Capsules 1 Capsule2 Capsules 1 Capsule  2 Capsules DAY 3 TO DAY 14 Amoxicillin VonoprazanBismuth Furazolidone Rifabutin Times 375 mg 20 mg 300 mg 100 mg 120 mg 8am 4 Capsules 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4 Capsules 1Capsule 2 Capsules 1 Capsule 0 8 pm 4 Capsules 1 Capsule 2 Capsules 1Capsule 1 Capsule C. Amoxicillin Vonoprazan Bismuth LevofloxacinRifabutin Times 375 mg 20 mg 300 mg 375 mg 60 mg DAY 1 8 am 4 Capsules 1Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4 Capsules 1 Capsule 2Capsules 0 0 8 pm 4 Capsules 1 Capsule 2 Capsules  2 Capsules 1 CapsuleDAY 2 8 am 4 Capsules 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4Capsules 1 Capsule 2 Capsules 0 0 8 pm 4 Capsules 1 Capsule 2 Capsules 2 Capsules  2 Capsules DAY 3 TO 14 Amoxicillin Vonoprazan BismuthLevofloxacin Rifabutin Times 375 mg 20 mg 300 mg 375 mg 120 mg 8 am 4Capsules 1 Capsule 2 Capsules 1 Capsule  1 Capsule 1 pm 4 Capsules 1Capsule 2 Capsules 0 0 8 pm 4 Capsules 1 Capsule 2 Capsules 2 Capsules 1Capsule D. Amoxicillin Vonoprazan Furazolidone Rifabutin Times 375 mg 20mg 100 mg 60 mg DAY 1 8 am 4 Capsules 1 Capsule 1 Capsule 1 Capsule 1 pm4 Capsules 1 Capsule 1 Capsule 0 8 pm 4 Capsules 1 Capsule 1 Capsule 1Capsule DAY 2 8 am 4 Capsules 1 Capsule 1 Capsule 1 Capsule 1 pm 4Capsules 1 Capsule 1 Capsule 0 8 pm 4 Capsules 1 Capsule 1 Capsule  2Capsules DAY 3 TO DAY 14 Amoxicillin Vonoprazan Furazolidone RifabutinTimes 375 mg 20 mg 100 mg 120 mg 8 am 4 Capsules 1 Capsule 1 Capsule 1Capsule 1 pm 4 Capsules 1 Capsule 1 Capsule 0 8 pm 4 Capsules 1 Capsule1 Capsule 1 Capsule E. Amoxicillin Vonoprazan Rifabutin LevofloxacinTimes 375 mg 20 mg 60 mg 375 mg 8 am 4 Capsules 1 Capsule 1 Capsule 1Capsule 1 pm 4 Capsules 1 Capsule 0 0 8 pm 4 Capsules 1 Capsule 1Capsule  2 Capsules DAY 2 8 am 4 Capsules 1 Capsule 1 Capsule 1 Capsule1 pm 4 Capsules 1 Capsule 0 0 8 pm 4 Capsules 1 Capsule  2 Capsules  2Capsules DAY 3 TO DAY 14 Amoxicillin Vonoprazan Rifabutin LevofloxacinTimes 375 mg 20 mg 120 mg 375 mg 8 am 4 Capsules 1 Capsule 1 Capsule 1Capsule 1 pm 4 Capsules 1 Capsule 0 0 8 pm 4 Capsules 1 Capsule 1Capsule  2 Capsules F. Amoxicillin Vonoprazan Bismuth FurazolidoneRifabutin Times 375 mg 20 mg 300 mg 100 mg 60 mg DAY 1 8 am 4 Capsules 1Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4 Capsules 1 Capsule 2Capsules 1 Capsule 0 8 pm 4 Capsules 1 Capsule 2 Capsules 1 Capsule 1Capsule DAY 2 8 am 4 Capsules 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1pm 4 Capsules 1 Capsule 2 Capsules 1 Capsule 0 8 pm 4 Capsules 1 Capsule2 Capsules 1 Capsule  2 Capsules DAY 3 TO DAY 14 Amoxicillin VonoprazanBismuth Furazolidone Rifabutin Times 375 mg 20 mg 300 mg 100 mg 120 mg 8am 4 Capsules 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4 Capsules 1Capsule 2 Capsules 1 Capsule 0 8 pm 4 Capsules 1 Capsule 2 Capsules 1Capsule 1 Capsule G. Amoxicillin Vonoprazan Bismuth LevofloxacinRifabutin Times 375 mg 20 mg 300 mg 375 mg 60 mg DAY 1 8 am 4 Capsules 1Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4 Capsules 1 Capsule 2Capsules 0 0 8 pm 4 Capsules 1 Capsule 2 Capsules  2 Capsules 1 CapsuleDAY 2 8 am 4 Capsules 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4Capsules 1 Capsule 2 Capsules 0 0 8 pm 4 Capsules 1 Capsule 2 Capsules 2 Capsules  2 Capsules DAY 3 TO 14 Amoxicillin Vonoprazan BismuthLevofloxacin Rifabutin Times 375 mg 20 mg 300 mg 375 mg 120 mg 8 am 4Capsules 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4 Capsules 1Capsule 2 Capsules 0 0 8 pm 4 Capsules 1 Capsule 2 Capsules  2 Capsules1 Capsule H. Amoxicillin Vonoprazan Furazolidone Bismuth RifabutinLevofloxacin Times 375 mg 20 mg 100 mg 300 mg 60 mg 375 mg DAY 1 8 am 4Capsules 1 Capsule 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4Capsules 1 Capsule 1 Capsule 2 Capsules 0 0 8 pm 4 Capsules 1 Capsule 1Capsule 2 Capsules 1 Capsule  2 Capsules DAY 2 8 am 4 Capsules 1 Capsule1 Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4 Capsules 1 Capsule 1Capsule 2 Capsules 0 0 8 pm 4 Capsules 1 Capsule 1 Capsule 2 Capsules  2Capsules  2 Capsules DAY 3 TO 14 Amoxicillin Vonoprazan FurazolidoneBismuth Rifabutin Levofloxacin Times 375 mg 20 mg 100 mg 300 mg 120 mg375 mg 8 am 4 Capsules 1 Capsule 1 Capsule 2 Capsules 1 Capsule 1Capsule 1 pm 4 Capsules 1 Capsule 1 Capsule 2 Capsules 0 0 8 pm 4Capsules 1 Capsule 1 Capsule 2 Capsules 1 Capsule  2 Capsules I.Amoxicillin Vonoprazan Bismuth Tetracycline Rifabutin Times 375 mg 20 mg300 mg 250 mg 60 mg DAY 1 8 am 4 Capsules 1 Capsule 2 Capsules 1 Capsule1 Capsule 1 pm 4 Capsules 1 Capsule 2 Capsules 1 Capsule 0 8 pm 4Capsules 1 Capsule 2 Capsules 1 Capsule 1 Capsule DAY 2 8 am 4 Capsules1 Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4 Capsules 1 Capsule 2Capsules 1 Capsule 0 8 pm 4 Capsules 1 Capsule 2 Capsules 1 Capsule  2Capsules DAY 3 TO 14 Amoxicillin Vonoprazan Bismuth TetracyclineRifabutin Times 375 mg 20 mg 300 mg 250 mg 120 mg 8 am 4 Capsules 1Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 4 Capsules 1 Capsule 2Capsules 1 Capsule 0 8 pm 4 Capsules 1 Capsule 2 Capsules 1 Capsule 1Capsule J. Metronidazole Vonoprazan Bismuth Tetracycline Rifabutin Times200 mg 20 mg 300 mg 250 mg 60 mg DAY 1 8 am 1 Capsule 1 Capsule 2Capsules 1 Capsule 1 Capsule 1 pm 1 Capsule 1 Capsule 2 Capsules 1Capsule 0 8 pm 1 Capsule 1 Capsule 2 Capsules 1 Capsule 1 Capsule DAY 28 am 1 Capsule 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 1 Capsule 1Capsule 2 Capsules 1 Capsule 0 8 pm 1 Capsule 1 Capsule 2 Capsules 1Capsule  2 Capsules DAY 3 TO 14 Metronidazole Vonoprazan BismuthTetracycline Rifabutin Times 200 mg 20 mg 300 mg 250 mg 120 mg 8 am 1Capsule 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 1 Capsule 1Capsule 2 Capsules 1 Capsule 0 8 pm 1 Capsule 1 Capsule 2 Capsules 1Capsule 1 Capsule K. Vonoprazan Bismuth Levofloxacin Rifabutin Times 20mg 300 mg 375 mg 60 mg 8 am 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1pm 1 Capsule 2 Capsules 0 0 8 pm 1 Capsule 2 Capsules  2 Capsules 1Capsule DAY 2 8 am 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 1Capsule 2 Capsules 0 0 8 pm 1 Capsule 2 Capsules  2 Capsules  2 CapsulesDAY 3 TO 14 Vonoprazan Bismuth Levofloxacin Rifabutin Times 20 mg 300 mg375 mg 120 mg 8 am 1 Capsule 2 Capsules 1 Capsule 1 Capsule 1 pm 1Capsule 2 Capsules 0 0 8 pm 1 Capsule 2 Capsules  2 Capsules 1 CapsuleL. Amoxicillin Vonoprazan Furazolidone Rifabutin Bismuth NitazoxanideTimes 375 mg 20 mg 100 mg 60 mg 300 mg 500 mg 8 am 4 Capsules 1 Capsule1 Capsule 1 Capsule 2 Capsules 1 Capsule 1 pm 4 Capsules 1 Capsule 1Capsule 0 2 Capsules 0 8 pm 4 Capsules 1 Capsule 1 Capsule 1 Capsule 2Capsules 1 Capsule DAY 2 8 am 4 Capsules 1 Capsule 1 Capsule 1 Capsule 2Capsules 1 Capsule 1 pm 4 Capsules 1 Capsule 1 Capsule 0 2 Capsules 0 8pm 4 Capsules 1 Capsule 1 Capsule  2 Capsules 2 Capsules 1 Capsule DAY 3TO DAY 14 Amoxicillin Vonoprazan Furazolidone Rifabutin BismuthNitazoxanide Times 375 mg 20 mg 100 mg 120 mg 300 mg 500 mg 8 am 4Capsules 1 Capsule 1 Capsule 1 Capsule 2 Capsules 1 Capsule 1 pm 4Capsules 1 Capsule 1 Capsule 0 2 Capsules 0 8 pm 4 Capsules 1 Capsule 1Capsule 1 Capsule 2 Capsules 1 Capsule

In alternative embodiments, therapeutic combination as provided herein,and as used to practice methods as provided herein, are formulated anddosaged for oral administration as a powder, e.g., a lyophilised powder,which can be inserted into carriers, e.g., capsules, tablets, geltabs,and the like, e.g., for administration to adults, infants or children toingest.

In alternative embodiments, therapeutic combination as provided herein,and as used to practice methods as provided herein, are formulated anddosaged for individuals at an age of 2.5 years or above, where thechildren are unlikely to be able to swallow a capsule; thus, thisprovided are additional delivery vehicles, products of manufacture anddevices to be combined with formulations as provided herein, e.g.,powders such as lyophilised powders, e.g., lyophilised powder in astorage vehicle, e.g., capsules, geltabs and the like; for example,provided are delivery vehicles, products of manufacture and devicesmanufactured as a container, a kit, a package or a pack of a “device andcapsule” together, e.g., operably associated such that the container,kit, package or a pack permits individuals, e.g., the very youngchildren and the older children (and including disabled or handicappedindividuals) to ingest the product, e.g., the lyophilised product, fromthe storage vehicle, e.g., capsules, geltabs and the like.

In alternative embodiments, the container, kit, a package or a packprovides the ability of any age child (or disabled or handicappedindividual, or any individual) to ingest or swallow the product (e.g., atherapeutic combination, a formulation, pharmaceutical preparation orpharmaceutical composition as provided herein) within the storagevehicle (e.g., capsule) by “draining”, e.g., by puncturing, crushing,twisting or turning the container by hand or a device, or otherwiseopening, the storage vehicle using a puncturing, crushing or equivalentdevice (operably built into the container, kit, package or pack), or byhand motion, e.g., by twisting or hand turning (e.g., by hand) thecontainer, and thus allowing passage or contact of the contents of thestorage vehicle to enter or pass into an ingestible liquid or otheredible substance (e.g., an ice cream or a yoghurt), which is alsocontained within the container, kit, package or pack, which can beinitially (before the twisting or turning, puncturing, crushing orotherwise opening) in a separate compartment from the storagecompartment. This twisting or turning, or puncturing, crushing orotherwise opening of the storage compartment and the passage or contactof the contents of the storage vehicle to the ingestible liquideffectively places the contents of the storage (e.g., a powder orfreeze-dry comprised of or within a formulation, pharmaceuticalpreparation or pharmaceutical composition as provided herein) into theingestible liquid or substance, which can be e.g., water, a milk, ayoghurt, an ice cream, a yogurt, a juice (e.g., a fruit juice, an applejuice), an apple sauce, or a masking drink. The container, kit, packageor pack can be designed as an infant feeding bottle, e.g., comprising anipple or teat for the very young.

In alternative embodiments, this simple twisting or turning, orpuncturing or crushing device, allows the storage containers, e.g.,geltabs or capsules, to be punctured and/or crushed or otherwise“opened”, allowing the contents of the storage container, (e.g., apowder or freeze-dry comprised of or within a therapeutic combination, aformulation, pharmaceutical preparation or pharmaceutical composition asprovided herein), to fall out in to the liquid or food compartment,e.g., to the bottom end of a device or straight into a bottle or acontainer held underneath or configured to be attached and underneath.For example, in this way a provider, e.g., the mother, can purchase asupply of storage containers, e.g., geltabs or capsules, convert them asneeded into a powder capable of being mixed a liquid of her choice thatthe child will be ingesting.

In alternative embodiments, for those capable of swallowing tablets,capsules and the like, the storage containers, e.g., geltabs, tablets orcapsules, are manufactured as enteric coated to bypass the acid of thestomach and bile of the duodenum, such that the storage containers,e.g., geltabs, tablets or capsules open (e.g., dissolve) in the jejunumor below.

In alternative embodiments, further provided are instructions for use,e.g., that when emptied into a drink, providers (e.g., the mothers ofinfants or children) are advised to choose a drink or food that has itsown buffering capacity such as flavoured milk, chocolate milk, icecream, yoghurt, ice blocks, frozen icicles, or simply milk, e.g., thatis being fed to the infant or child by a bottle, e.g., a milk bottle,with a nipple or teat.

In alternative embodiments, storage containers, e.g., geltabs, tabletsor capsules, or any formulation as provided herein, also comprises anantacid, e.g., a calcium carbonate, magnesium hydroxide, propyleneglycol alginate and sodium alginate, or the combination of aluminiumhydroxide with magnesium tri silicate, magnesium oxide or magnesiumcarbonate, so that when the storage container is punctured, crushed orotherwise opened and put into contact with the liquid, e.g., the feedingbottle, and ingested, there will be greater protection from acid damage.In alternative embodiments, methods and instructions further comprisethe infant or child also being given an acid suppressant beforehand topermit more viable living bacteria to arrive in the colon.

In alternative embodiments, therapeutic combinations, formulations,pharmaceuticals or pharmaceutical preparations as provided herein areformulated or manufactured as storage vehicles, e.g., tablets, geltabs,pills, capsules and the like; and in alternative embodiments, thesestorage vehicles are contained in, or contained in a kit with, orpackaged with, or sold together with, a storage vehicle ‘cracking’,puncturing, or otherwise opening or releasing device (e.g., as a powder,e.g., as lyophilised material). These can be dispensed together, orconfigured together, or manufactured together, as a simple way ofmeeting the needs of both infants, the very young, older children andneedful (e.g., handicapped) adults; e.g., as a powder, e.g., aslyophilised material, e.g., from their storage vehicles, e.g., asencapsulated therapeutic combinations, formulations, pharmaceuticals orpharmaceutical preparations, thus permitting successful clinicaladministration on a frequent, e.g., bid, tid, or daily, basis forprolonged periods.

Methods of Use and Applications of Devices and Therapeutic CombinationsMulticomponent Packaging

Provided are multi-component delivery systems, e.g., products ofmanufacture, comprising e.g., formulations, pharmaceutical preparationsor pharmaceutical compositions used to practice methods as providedherein, e.g., formulated and dosaged for oral administration as apowder, e.g., a lyophilised powder, and another component, e.g., aliquid; these multi-component delivery systems, e.g., products ofmanufacture, can be designed or manufactured as described e.g., in U.S.Pat. Nos. 8,968,717; 8,931,665; 7,861,854; 7,018,089; 6,626,912; and,U.S. Pat. App. Pub nos. 2010/0034574; 2009/0180923; 20090232886;2008/0160076; 2007/0087048; 2007/0036830; 2007/0074979; 2005/0205438;2004/0089563.

Packaging

Provided are compositions, including preparations, formulations and/orkits, comprising combinations of ingredients, e.g., therapeuticcombinations as described herein. In alternative embodiments,therapeutic combination can be mixed and administered together, oralternatively, they can be an individual member of a packagedcombination of ingredients, e.g., a liquid component and a solid productcomponent manufactured in a separate compartment, package, kit orcontainer; e.g., where all or a subset of the combinations ofingredients are manufactured in a separate compartment, package orcontainer. In alternative aspects, the package, kit or containercomprises a blister package, a clamshell, a tray, a shrink wrap and thelike.

In one aspect, the package, kit or container comprises a “blisterpackage” (also called a blister pack, or bubble pack). In one aspect,the blister package is made up of two separate elements: a transparentplastic cavity shaped to the product and its blister board backing.These two elements are then joined together with a heat sealing processwhich allows the product to be hung or displayed. Exemplary types of“blister packages” include: Face seal blister packages, gang run blisterpackages, mock blister packages, interactive blister packages, slideblister packages.

Blister packs, clamshells or trays are forms of packaging used forgoods; thus, provided are for blister packs, clamshells or trayscomprising a formulations, pharmaceutical preparations or pharmaceuticalcompositions used to practice methods as provided herein. Blister packs,clamshells or trays can be designed to be non-reclosable, so consumerscan tell if a package has already opened. They are used to package forsale goods where product tampering is a consideration, such as thepharmaceuticals as provided herein. In one aspect, a blister packcomprises a moulded PVC base, with raised areas (the “blisters”) tocontain the tablets, pills, etc. comprising the combinations offormulations, pharmaceutical preparations or pharmaceutical compositionsas provided herein, covered by a foil laminate. Tablets, pills, etc. areremoved from the pack either by peeling the foil back or by pushing theblister to force the tablet to break the foil. In one aspect, aspecialized form of a blister pack is a strip pack. In one aspect, inthe United Kingdom, blister packs adhere to British Standard 8404.

In one embodiment, provided is a method of packaging wherein thecompositions comprising combinations of ingredients are containedin-between a card and a clear PVC. The PVC can be transparent so theitem (pill, tablet, geltab, etc.) can be seen and examined easily; andin one aspect, can be vacuum-formed around a mould so it can contain theitem snugly and have room to be opened upon purchase. In one aspect, thecard is brightly colored and designed depending on the item (pill,tablet, geltab, etc.) inside, and the PVC is affixed to the card usingpre-formed tabs where the adhesive is placed. The adhesive can be strongenough so that the pack may hang on a peg, but weak enough so that thisway one can tear open the join and access the item. Sometimes with largeitems or multiple enclosed pills, tablets, geltabs, etc., the card has aperforated window for access. In one aspect, more secure blister packs,e.g., for items such as pills, tablets, geltabs, etc. are used, and theycan comprise of two vacuum-formed PVC sheets meshed together at theedges, with the informative card inside. These can be hard to open byhand, so a pair of scissors or a sharp knife may be required to open.

In one aspect, blister packaging comprises at least two or three or morecomponents: a thermoformed “blister” which houses multi-ingredientcombination as provided herein, and then a “blister card” that is aprinted card with an adhesive coating on the front surface. During theassembly process, the blister component, which is most commonly made outof PVC, is attached to the blister card using a blister machine. Thismachine introduces heat to the flange area of the blister whichactivates the glue on the card in that specific area and ultimatelysecures the PVG blister to the printed blister card. The thermoformedPVG blister and the printed blister card can be as small or as large asyou would like, but there are limitations and cost considerations ingoing to an oversized blister card. Conventional blister packs can alsobe sealed (e.g., using an AERGO 8 DUO™, SCA Consumer Packaging, Inc.,DeKalb Ill.) using regular heat seal tooling. This alternative aspect,using heat seal tooling, can seal common types of thermoformedpackaging.

In alternative embodiments, therapeutic combinations, formulations,pharmaceutical preparations or pharmaceutical compositions areformulated, e.g., as a powder, e.g., as lyophilised material, e.g., alyophilized encapsulated product, e.g., for practicing methods asprovided herein, can be packaged alone or in combinations, e.g., as“blister packages” or as a plurality of packettes, including as liddedblister packages, lidded blister or blister card or packets orpackettes, or a shrink wrap.

In alternative embodiments, laminated aluminium foil blister packs areused, e.g., for the preparation of therapeutic combinations,formulations, pharmaceutical preparations or pharmaceutical compositionsas provided herein. Products or kits comprise an aqueous solution(s)which are dispensed (e.g., by measured dose) into containers. Trays canbe freeze-dried to form tablets which take the shape of the blisterpockets. The alufoil laminate of both the tray and lid fully protectsany highly hygroscopic and/or sensitive individual doses. In one aspect,the pack incorporates a child-proof peel open security laminate. In oneaspect, the system give tablets an identification mark by embossing adesign into the alufoil pocket that is taken up by the tablets when theychange from aqueous to solid state. In one aspect, individual‘push-through’ blister packs/ packettes are used, e.g., using hardtemper aluminium (e.g., alufoil) lidding material. In one aspect,hermetically-sealed high barrier aluminium (e.g., alufoil) laminates areused. In one aspect, products of manufacture include kits or blisterpacks, use foil laminations and strip packs, stick packs, sachets andpouches, peelable and non-peelable laminations combining foil, paper, orfilm for high barrier packaging.

Products of manufacture and Kits

Provided are products of manufacture and kits for practicing methods asprovided herein, comprising a therapeutic combination, a formulation, apharmaceutical preparation or a pharmaceutical composition as providedherein.

In alternative embodiments, multi-component products of manufacture,including kits or blister packs as provided herein, include memory aidsto help remind patients when and how to take the therapeuticcombination. This safeguards the therapeutic combination's efficacy byprotecting each tablet, geltab or pill until it's taken; gives theproduct or kit portability, makes it easy to take a dose anytime oranywhere.

The invention will be further described with reference to the examplesdescribed herein; however, it is to be understood that the invention isnot limited to such examples.

A number of embodiments of the invention have been described.Nevertheless, it can be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

EXAMPLES

A 47 year old male allergic to penicillin, was referred after fivedifferent therapies had failed to eradicate H. pylori and he was stillsymptomatic. To better enhance eradication and dissolve the biofilm hewas pre-treated with Bifidobacterium infantum three times daily for 4weeks and this was continued for the next 10 days during the antibiotictreatment. The antibiotic treatment comprised [all ×3 per day]vonoprazan 20 mg; metronidazole 400 mg; bismuth subsalicylate 300 mg;tetracycline HCl 400 mg; and rifabutin 150 mg. When retested by ureabreath test 4 weeks after ceasing therapy, the test was negative,showing eradication of the bacteria.

A number of embodiments of the invention have been described.Nevertheless, it can be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

What is claimed is:
 1. A method for treating, ameliorating, reversingand/or preventing, or acting as a prophylaxis, a Helicobacter pylori (H.pylori) infection in an individual in need thereof, comprising:administering to the individual in need thereof a therapeuticcombination comprising: (A) (a) a composition comprising or consistingof: vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™; and (b) an antimicrobial or antibioticdrug or composition comprising or consisting of: (i) (1) an amoxicillin,administered to the individual in need thereof at a dose of betweenabout 1 gram (g) to about 2 g twice daily (bid), optionally theamoxicillin is formulated as amoxicillin/ clavulanic acid, also known asco-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™,AMOXIL™, TRIMOX™; and (2) a clarithromycin, optionally BIAXIN™,administered to the individual in need thereof at a dose of betweenabout 100 mg to about 2 g twice daily, wherein the vonoprazan or avonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 20 mg to about 50 mg twice daily(bid), or for about 25 mg or more twice daily (bid); (ii) (1) anamoxicillin, administered to the individual in need thereof at a dose ofbetween about 500 gm to about 1 g three times daily (tid), andoptionally the amoxicillin is formulated as amoxicillin/ clavulanicacid, al so known as co-amoxiclav, or is optionally ACTIMOXI™,ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and (2) a metronidazole,optionally FLAGYL™, METRO™, administered to the individual in needthereof at a dose of between about 200 mg to about 500 mg three timesdaily (tid), wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 20 mg to about 50 mg three times daily(tid), or for about 25 mg or more three times daily (tid); (iii) (1) anamoxicillin, administered to the individual in need thereof at a dose ofbetween about 250 gm to about 1 g twice daily (bid) or three times daily(tid), and optionally the amoxicillin is formulated asamoxicillin/clavulanic acid, also known as co-amoxiclav, or isoptionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and(2) a rifabutin, optionally MYCOBUTIN™, administered to the individualin need thereof at a dose of between about 50 mg to about 250 mg twicedaily (bid) or three times daily (tid), wherein the vonoprazan or avonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 200 mg or more twicedaily (bid) or three times daily (tid); (iv) (1) an amoxicillin,administered to the individual in need thereof at a dose of betweenabout 250 gm to about 1 g twice daily (bid) or three times daily (tid),and optionally the amoxicillin is formulated as amoxicillin/clavulanicacid, also known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and (2) a levofloxacin, administeredto the individual in need thereof at a dose of between about 100 mg toabout 500 mg twice daily (bid) or three times daily (tid), wherein thevonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 200 mg or more twicedaily (bid) or three times daily (tid); (v) (1) an amoxicillin,administered to the individual in need thereof at a dose of betweenabout 250 gm to about 1 g twice daily (bid) or three times daily (tid),and optionally the amoxicillin is formulated as amoxicillin/clavulanicacid, also known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and (2) a ciprofloxacin, optionallyCILOXAN™, CIPRO™, NEOFLOXIN™ administered to the individual in needthereof at a dose of between about 100 mg to about 500 mg twice daily(bid) or three times daily (tid), wherein the vonoprazan or a vonoprazanfumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 200 mg or more twicedaily (bid) or three times daily (tid); (vi) (1) an amoxicillin,administered to the individual in need thereof at a dose of betweenabout 250 gm to about 1 g twice daily (bid) or three times daily (tid),and optionally the amoxicillin is formulated as amoxicillin/clavulanicacid, also known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and (2) a moxifloxacin, optionallyAVELOX™, VIGAMOX™, MOXEZA™ administered to the individual in needthereof at a dose of between about 25 mg to about 500 mg per day,wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 200 mg or more twicedaily (bid) or three times daily (tid); (vii) (1) an amoxicillin, aclarithromycin, a metronidazole, a levofloxacin, a ciprofloxacin or amoxifloxacin, administered to the individual in need thereof at a doseas set forth in any of steps (i) to (vi), optionally the amoxicillin isformulated as amoxicillin/ clavulanic acid, also known as co-amoxiclav,or is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™,TRIMOX™; and (2) a TG44, or a 1-1000 mg/d] {[4-methylbenzyl4′-[trans-4-(guanidine-methyl) cyclohexylcarbonyloxy]biphenyl-4-carboxylate monohydrochloride}, or CAS registrynumber 178748-55-5, administered to the individual in need thereof at adose of between about 15 mg to about 50 mg per day, or at about 50 to500 mg per day, wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose of between 5 mg to about 50 mg, or 20 mg or more,twice daily (bid) or three times daily (tid); (viii) (1) an amoxicillin,(2) a furazolidone, optionally FUROXONE™, DEPENDAL-M™, administered tothe individual in need thereof at a dose of between about 50 to about600 mg/d, and (3) a rifabutin, optionally MYCOBUTIN™, administered tothe individual in need thereof at a dose of between about 60 to about450 mg/d, and optionally the rifabutin dose is ramped up starting atabout 40 to about 60 g bid or tid, and optionally rising over 3 days toabout 200 to about 450/d, wherein the vonoprazan or a vonoprazanfumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof at a dose as set forth in any of (i) to (vii); (ix) atherapeutic combination as set forth in Table 1; or (x) any combinationof (i) to (ix); or (B) (a) vonoprazan, and (b) a prolonged releaseformulation comprising an antibiotic comprising: (1) amoxicillin whereinoptionally the amoxicillin is formulated as amoxicillin/clavulanic acid,and/or (2) an antibiotic selected from the group consisting ofclarithromycin, azithromycin, roxithromycin and erythromycin, whereinthe vonoprazan is administered in an amount of 10 mg to 1 g per day, andthe amoxicillin is administered in an amount of 10 mg to 6 g per day;or, (C) (a) a prolonged release microencapsulated and/or multimatrixformulation comprising vonoprazan, and (b) a prolonged releasemicroencapsulated and/or multimatrix formulation comprising amoxicillinwherein optionally the amoxicillin is formulated asamoxicillin/clavulanic acid, or (c) a prolonged releasemicroencapsulated and/or multimatrix formulation comprising vonoprazanand amoxicillin wherein optionally the amoxicillin is formulated asamoxicillin/clavulanic acid, wherein the vonoprazan is administered inan amount of 10 mg to 1 g per day, and the amoxicillin is administeredin an amount of 1 g to 6 g per day; or (D) (a) vonoprazan, (b) a protonpump inhibitor, and (c) at least one antibiotic selected from the groupconsisting of amoxicillin, wherein optionally the amoxicillin isformulated as amoxicillin/clavulanic acid, ampicillin, pivampicillin,hetacillin, bacampicillin, metampicillin, talampicillin, epicillin, amacrolide antibiotic, furazolidone, ciprofloxacin, levofloxacin,tetracycline, a nitroimidazole antibiotic, bismuth, an ansamycinantibiotic, and nitazoxanide, wherein optionally the proton pumpinhibitor is selected from the group consisting of omeprazole;pantoprazole; esomeprazole, lansoprazole, and rabeprazole, whereinoptionally the macrolide antibiotic is selected from the groupconsisting of azithromycin, clarithromycin, erythromycin, fidaxomicin,and telithromycin, wherein optionally the nitroimidazole antibiotic isselected from the group consisting of metronidazole, tinidazole, andsecnidazole, wherein optionally the ansamycin antibiotic is selectedfrom the group consisting of rifabutin, rifampicin, rifapentin, andrifamixin; or (E) (i) amoxicillin, vonoprazan, furazolidone, andrifabutin; (ii) amoxicillin, vonoprazan, bismuth, furazolidone,rifabutin; (iii) amoxicillin, vonoprazan, bismuth, levofloxacin,rifabutin; (iv) amoxicillin, vonoprazan, levofloxacin, rifabutin; (v)amoxicillin, vonoprazan, bismuth, levofloxacin, furazolidone, rifabutin;(v) amoxicillin, vonoprazan, bismuth, tetracycline, rifabutin; (vi)metronidazole, vonoprazan, bismuth, tetracycline, rifabutin; (v)vonoprazan, bismuth, levofloxacin, rifabutin; or (vi) amoxicillin,vonoprazan, furazolidone, rifabutin, bismuth, and nitazoxanide, whereinoptionally the amoxicillin is formulated as amoxicillin/clavulanic acid.2. The method of claim 1, wherein the therapeutic combination isadministered to the individual in need thereof for about 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13 or 14 or more days.
 3. The method of claim 1,wherein the therapeutic combination is, is contained in or comprises aformulation, a pharmaceutical preparation or a pharmaceuticalcomposition.
 4. The method of claim 1, wherein the vonoprazan orvonoprazan fumarate, or the5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or the1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is administered to the individual inneed thereof: (a) at a unit dosage of between about 5 mg to about 200 mgper day, or (b) in a unit dosage form of between about 10 mg and 200mgm, or between about between about 40 mg and 100 mgm, or is about 10,20, 30, 40, 50, 60, 70, 75, 80, 90 or 100 mg per unit dose, whichoptionally can be administered once a day, bid or tid, or four times aday, five times a day or six times a day or more, regimen.
 5. The methodof claim 1, wherein therapeutic combination, or the formulation, thepharmaceutical or the pharmaceutical preparation, is formulated as achewable delivery vehicle, a gum, a gummy, a candy, a lozenge, an icecream or an ice, or a yogurt.
 6. The method of claim 1, whereintherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, further comprises a flavoring or asweetening agent, an aspartamine, a stevia, monk fruit, a sucralose, asaccharin, a cyclamate, a xylitol, a vanilla, an artificial vanilla orchocolate or strawberry flavor, an artificial chocolate essence, or amixture or combination thereof.
 7. The method of claim 1, whereintherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, further comprises a preservative, a benzoicacid or a potassium sorbate.
 8. The method of claim 1, whereintherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, further comprises, or has added to: at leastone probiotic or prebiotic, wherein optionally the prebiotic comprisesan inulin, lactulose, extracts of artichoke, chicory root, oats, barley,various legumes, garlic, kale, beans or flax or an herb, whereinoptionally the probiotic comprises a cultured or stool-extractedmicroorganism or bacteria, or a bacterial component, and optionally thebacteria or bacterial component comprises or is derived from aSaccharomyces boulardii, Bacteroidetes, a Firmicutes, a Lactobacilli, aBifidobacteria, an E. coli, a Strep fecalis and equivalents.
 9. Themethod of claim 1, wherein therapeutic combination, or the formulation,the pharmaceutical or the pharmaceutical preparation, further comprises,or has added to: at least one congealing agent, wherein optionally thecongealing agent comprises an arrowroot or a plant starch, a powderedflour, a powdered potato or potato starch, an absorbant polymer, anAbsorbable Modified Polymer, and/or a corn flour or a corn starch. 10.The method of claim 1, wherein therapeutic combination, or theformulation, the pharmaceutical or the pharmaceutical preparation,further comprises an additive selected from one or more of a saline, amedia, a defoaming agent, a surfactant agent, a lubricant, an acidneutralizer, a marker, a cell marker, a drug, an antibiotic, a contrastagent, a dispersal agent, a buffer or a buffering agent, a sweeteningagent, a debittering agent, a flavoring agent, a pH stabilizer, anacidifying agent, a preservative, a desweetening agent and/or coloringagent, vitamin, mineral and/or dietary supplement, or a prebioticnutrient.
 11. The method of claim 1, wherein therapeutic combination, orthe formulation, the pharmaceutical or the pharmaceutical preparation,further comprises, or has added to: at least one Biofilm DisruptingCompound, wherein optionally the biofilm disrupting compound comprisesan enzyme, a deoxyribonuclease (DNase), N-acetylcysteine, an auranofin,an alginate lyase, glycoside hydrolase dispersin B; a Quorum-sensinginhibitor, a ribonucleic acid III inhibiting peptide, Salvadora persicaextracts, Competence-stimulating peptide, Patulin and penicillic acid;peptides—cathelicidin-derived peptides, small lytic peptide, PTP-7,Nitric oxide, neo-emulsions; ozone, lytic bacteriophages, lactoferrin,xylitol hydrogel, synthetic iron chelators, cranberry components,curcumin, silver nanoparticles, Acetyl-11-keto-β-boswellic acid (AKBA),barley coffee components, probiotics, sinefungin, S-adenosylmethionine,S-adenosyl-homocysteine, Delisea furanones, N-sulfonyl homoserinelactones or any combination thereof.
 12. The method of claim 1, whereintherapeutic combination, or the formulation, the pharmaceutical or thepharmaceutical preparation, further comprises, or has added to a statinselected from the group consisting of atorvastatin, fluvastatin,lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.13. The method of claim 1, wherein therapeutic combination, or theformulation, the pharmaceutical or the pharmaceutical preparation,further comprises, or has added to a pronase.
 14. The method of claim 1,wherein therapeutic combination, or the formulation, the pharmaceuticalor the pharmaceutical preparation, is formulated as a delayed or gradualenteric release composition or formulation, and optionally theformulation comprises a gastro-resistant coating designed to dissolve ata pH of 7 in the terminal ileum, e.g., an active ingredient is coatedwith an acrylic based resin or equivalent, e.g., a poly(meth)acrylate,e.g. a methacrylic acid copolymer B, NF, which dissolves at pH 7 orgreater, e.g., comprises a multimatrix (MMX) formulation.
 15. The methodof claim 1, wherein therapeutic combination, or the formulation, thepharmaceutical or the pharmaceutical preparation, is: (a) contained in adelivery vehicle, product of manufacture, container, syringe, device orbag; (b) initially manufactured or formulated as a liquid, a suspension,a gel, a geltab, a semisolid, a tablet, a sachet, a lozenge or acapsule, or as an enteral formulation, or re-formulated for finaldelivery as a liquid, a suspension, a gel, a geltab, a semisolid, atablet, a sachet, a lozenge or a capsule, or as an enteral formulation.16. A therapeutic combination comprising: (a) a composition comprisingor consisting of: vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™; and (b) an antimicrobial or antibioticdrug or composition comprising or consisting of: (i) (1) an amoxicillin,formulated for administration to the individual in need thereof at adose of between about 1 gram (g) to about 2 g twice daily (bid), andoptionally the amoxicillin is formulated as amoxicillin/ clavulanicacid, also known as co-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™,AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and (2) a clarithromycin, optionallyBIAXIN™, formulated for administration to the individual in need thereofat a dose of between about 100 mg to about 2 g twice daily, wherein thevonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration to theindividual in need thereof at a dose of between 20 mg to about 50 mgtwice daily (bid), or for about 25 mg or more twice daily (bid); (ii)(1) an amoxicillin, formulated for administration to the individual inneed thereof at a dose of between about 500 gm to about 1 g three timesdaily (tid), and optionally the amoxicillin is formulated asamoxicillin/clavulanic acid, also known as co-amoxiclav, or isoptionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and(2) a metronidazole, optionally FLAGYL™, METRO™, formulated foradministration to the individual in need thereof at a dose of betweenabout 200 mg to about 500 mg three times daily (tid), wherein thevonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration to theindividual in need thereof at a dose of between 20 mg to about 50 mgthree times daily (tid), or for about 25 mg or more three times daily(tid); (iii) (1) an amoxicillin, formulated for administration to theindividual in need thereof at a dose of between about 250 gm to about 1g twice daily (bid) or three times daily (tid), and optionally theamoxicillin is formulated as amoxicillin/clavulanic acid, also known asco-amoxiclav, or is optionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™,AMOXIL™, TRIMOX™; and (2) a rifabutin, optionally MYCOBUTIN™, formulatedfor administration to the individual in need thereof at a dose ofbetween about 50 mg to about 250 mg twice daily (bid) or three timesdaily (tid), wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration to theindividual in need thereof at a dose of between 5 mg to about 200 mg ormore twice daily (bid) or three times daily (tid); (iv) (1) anamoxicillin, formulated for administration to the individual in needthereof at a dose of between about 250 gm to about 1 g twice daily (bid)or three times daily (tid), and optionally the amoxicillin is formulatedas amoxicillin/clavulanic acid, also known as co-amoxiclav, or isoptionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and(2) a levofloxacin, formulated for administration to the individual inneed thereof at a dose of between about 100 mg to about 500 mg twicedaily (bid) or three times daily (tid), wherein the vonoprazan or avonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration to theindividual in need thereof at a dose of between 5 mg to about 200 mg ormore twice daily (bid) or three times daily (tid); (v) (1) anamoxicillin, formulated for administration to the individual in needthereof at a dose of between about 250 gm to about 1 g twice daily (bid)or three times daily (tid), and optionally the amoxicillin is formulatedas amoxicillin/ clavulanic acid, also known as co-amoxiclav, or isoptionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and(2) a ciprofloxacin, optionally CILOXAN™, CIPRO™, NEOFLOXIN™ formulatedfor administration to the individual in need thereof at a dose ofbetween about 100 mg to about 500 mg twice daily (bid) or three timesdaily (tid), wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration to theindividual in need thereof at a dose of between 5 mg to about 200 mg ormore twice daily (bid) or three times daily (tid); (vi) (1) anamoxicillin, formulated for administration to the individual in needthereof at a dose of between about 250 gm to about 1 g twice daily (bid)or three times daily (tid), and optionally the amoxicillin is formulatedas amoxicillin/clavulanic acid, also known as co-amoxiclav, or isoptionally ACTIMOXI™, ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and(2) a moxifloxacin, optionally AVELOX™, VIGAMOX™, MOXEZA™ formulated foradministration to the individual in need thereof at a dose of betweenabout 25 mg to about 500 mg per day, wherein the vonoprazan or avonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration to theindividual in need thereof at a dose of between 5 mg to about 200 mg ormore twice daily (bid) or three times daily (tid); (vii) (1) anamoxicillin, a clarithromycin, a metronidazole, a levofloxacin, aciprofloxacin or a moxifloxacin, formulated for administration to theindividual in need thereof at a dose as set forth in any of steps (i) to(vi), and optionally the amoxicillin is formulated as amoxicillin/clavulanic acid, also known as co-amoxiclav, or is optionally ACTIMOXI™,ALPHAMOX™, AMOCLA™, TYCIL™, AMOXIL™, TRIMOX™; and (2) a TG44, or a1-1000 mg/d] {[4-methylbenzyl 4′-[trans-4-(guanidine-methyl) cyclohexylcarbonyloxy]biphenyl-4-carboxylate monohydrochloride}, or CAS registrynumber 178748-55-5, formulated for administration to the individual inneed thereof at a dose of between about 15 mg to about 50 mg per day, orat about 50 to 500 mg per day, wherein the vonoprazan or a vonoprazanfumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration to theindividual in need thereof at a dose of between 5 mg to about 50 mg, or20 mg or more, twice daily (bid) or three times daily (tid); (viii) (1)an amoxicillin, (2) a furazolidone, optionally FUROXONE™, DEPENDAL-M™,formulated for administration to the individual in need thereof at adose of between about 50 to about 600 mg/d, and (3) a rifabutin,optionally MYCOBUTIN™, formulated for administration to the individualin need thereof at a dose of between about 60 to about 450 mg/d, andoptionally the rifabutin dose is ramped up starting at about 40 to about60 g bid or tid, and optionally rising over 3 days to about 200 to about450/d, wherein the vonoprazan or a vonoprazan fumarate, or a5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanaminemonofumarate, or a1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methyl-methanaminefumarate), optionally TAKECAB™, is formulated for administration to theindividual in need thereof at a dose as set forth in any of (i) to(vii); (ix) a therapeutic combination as set forth in Table 1; or (x)any combination of (i) to (ix).
 17. A kit or product of manufacturecomprising a therapeutic combination of claim 16.